Breast cancer laboratory tests: Difference between revisions

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Revision as of 14:19, 19 April 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2] Mirdula Sharma, MBBS [3]l; Ammu Susheela, M.D. [4]

Overview

Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1and 2, HER2), multiple gene panels (i.e. Oncotype DX), tumor markers (Ki67), and metastatic markers such as serum alkaline phosphatase as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests (alanine aminotransferase (ALT), aspartate transaminase (AST) , bilirubin, alkaline phosphatase) and markers of kidney function (BUN, creatinine).

BRCA1/BRCA2

Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence.

BRCA1

The human BRCA1 gene is located on the long (q) arm of chromosome 17 at region 2 band 1, from base pair 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) (map).^[1] BRCA1 orthologs have been identified in most vertebrates for which complete genome data are available ^[2].

Function and mechanism

BRCA1 is part of a complex that repairs double-strand breaks in DNA. The strands of the DNA double helix are continuously breaking as they become damaged. Sometimes only one strand is broken, sometimes both strands are broken simultaneously. DNA cross-linking agents are an important source of chromosome/DNA damage. Double-strand breaks occur as intermediates after the crosslinks are removed, and indeed, biallelic mutations in BRCA1 have been identified to be responsible for Fanconi Anemia, Complementation Group S,^[3] a genetic disease associated with hypersensitivity to DNA crosslinking agents. BRCA1 is part of a protein complex that repairs DNA when both strands are broken. When this happens, it is difficult for the repair mechanism to "know" how to replace the correct DNA sequence, and there are multiple ways to attempt the repair. The double-strand repair mechanism in which BRCA1 participates is homology-directed repair, where the repair proteins copy the identical sequence from the intact sister chromatid.^[4]

In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.^[5] These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.^{[citation needed]}

BRCA1 is also involved in another type of DNA repair, termed mismatch repair. BRCA1 interacts with the DNA mismatch repair protein MSH2.^[6] MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.^[7]

A protein called valosin-containing protein (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites. After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.^[8] BRCA1 interacts with VCP.^[9] BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.^[10]

BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.^[11] This may explain a role for BRCA1 to promote lower fidelity DNA repair by non-homologous end joining (NHEJ).^[12] BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.^[13]^[14]

Formaldehyde and acetaldehyde are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.^[15]^[16]

This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was hypomorphic.^[17]

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.^[18]

These mutations can be changes in one or a small number of DNA base pairs (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.^{[citation needed]}

In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation.^[19] Other methods have been proposed: traditional quantitative PCR,^[20] Multiplex Ligation-dependent Probe Amplification (MLPA),^[21] and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).^[22] Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).^[23]

Some results suggest that hypermethylation of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.^[24]

A mutated BRCA1 gene usually makes a protein that does not function properly. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.^{[citation needed]}

BRCA1 mRNA 3' UTR can be bound by an miRNA, Mir-17 microRNA. It has been suggested that variations in this miRNA along with Mir-30 microRNA could confer susceptibility to breast cancer.^[25]

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.^[26]

Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.^[27]

Low expression of BRCA1 in breast and ovarian cancers

BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.^[28] It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues. In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.^[29] Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.^[30] Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.^[30]

Similarly, BRCA1 expression is low in the majority (55%) of sporadic epithelial ovarian cancers (EOCs) where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.^[31] In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.^[32] Bowtell^[33] reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic. In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy. Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.

Mutation of BRCA1 in breast and ovarian cancer

Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.^[34] Similarly, BRCA1 mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).^[35]

Thus, while BRCA1 expression is low in the majority of these cancers, BRCA1 mutation is not a major cause of reduced expression.

BRCA1 promoter hypermethylation in breast and ovarian cancer

BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.^[36] Similarly, BRCA1 promoter hypermethylation was present in only 5% to 15% of EOC cases.^[31]

Thus, while BRCA1 expression is low in these cancers, BRCA1 promoter methylation is only a minor cause of reduced expression.

MicroRNA repression of BRCA1 in breast cancers

There are a number of specific microRNAs, when overexpressed, that directly reduce expression of specific DNA repair proteins (see MicroRNA section DNA repair and cancer) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.^[37] Breast cancers can be classified based on receptor status or histology, with triple-negative breast cancer (15%–25% of breast cancers), HER2+ (15%–30% of breast cancers), ER+/PR+ (about 70% of breast cancers), and Invasive lobular carcinoma (about 5%–10% of invasive breast cancer). All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.^[38] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.^[37] Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.

In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.^[39] Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

MicroRNA repression of BRCA1 in ovarian cancers

In both serous tubal intraepithelial carcinoma (the precursor lesion to high grade serous ovarian carcinoma (HG-SOC)), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.^[40] In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).^[40] Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.

Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.^[31] Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,^[31] so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.

Population or subgroup	BRCA1 mutation(s)^[41]	Reference(s)
African-Americans	943ins10, M1775R	^[42]
Afrikaners	E881X	^[43]
Ashkenazi Jewish	185delAG, 188del11, 5382insC	^[44]^[45]
Austrians	2795delA, C61G, 5382insC, Q1806stop	^[46]
Belgians	2804delAA, IVS5+3A>G	^[47]^[48]
Dutch	Exon 2 deletion, exon 13 deletion, 2804delAA	^[47]^[49]^[50]
Finns	3745delT, IVS11-2A>G	^[51]^[52]
French	3600del11, G1710X	^[53]
French Canadians	C4446T	^[54]
Germans	5382insC, 4184del4	^[55]^[56]
Greeks	5382insC	^[57]
Hungarians	300T>G, 5382insC, 185delAG	^[58]
Italians	5083del19	^[59]
Japanese	L63X, Q934X	^[60]
Native North Americans	1510insG, 1506A>G	^[61]
Northern Irish	2800delAA	^[62]
Norwegians	816delGT, 1135insA, 1675delA, 3347delAG	^[63]^[64]
Pakistanis	2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G	^[65]
Polish	300T>G, 5382insC, C61G, 4153delA	^[66]^[67]
Russians	5382insC, 4153delA	^[68]
Scottish	2800delAA	^[62]^[69]
Spanish	R71G	^[70]^[71]
Swedish	Q563X, 3171ins5, 1201del11, 2594delC	^[42]^[72]

BRCA2

HER2

ERBB2 is a gene that has changed (mutated) so it helps a tumor grow oncogene. It is more commonly known as HER2 (or HER2/neu). HER2 stands for human epidermal growth factor receptor 2.^[73]
HER2 status testing is done to find out the amount of HER2 produced by a breast tumor.

Multiple gene panels

Oncotype DX®
MammaPrint®

Blood chemistry

Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. ^[73]

Urea (blood urea nitrogen or BUN) and creatinine may be measured to check kidney function. Kidney function is checked before chemotherapy is given and may be rechecked during or after treatment.
Alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase may be measured to check liver function.

Increased levels could indicate that cancer has spread to the liver.

Alkaline phosphatase can also be used to check for cancer in the bone.

Increased levels could indicate that cancer has spread to the bone.
Tumor markers such as Ki67

References

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↑
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↑
↑
↑ Wagner TM, Möslinger RA, Muhr D, Langbauer G, Hirtenlehner K, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Ropp E, Kubista E, Amirimani B, Helbich T, Becherer A, Scheiner O, Breiteneder H, Borg A, Devilee P, Oefner P, Zielinski C (1998). "BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics". International Journal of Cancer. 77 (3): 354–360. doi:10.1002/(SICI)1097-0215(19980729)77:3<354::AID-IJC8>3.0.CO;2-N. PMID 9663595.
↑ ^47.0 ^47.1 Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, van der Luijt R, van der Hout AH, Gille JJ, Pals G, Jedema I, Olmer R, van Leeuwen I, Newman B, Plandsoen M, van der Est M, Brink G, Hageman S, Arts PJ, Bakker MM, Devilee P (1997). "A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families". American Journal of Human Genetics. 60 (5): 1041–1049. PMC 1712432. PMID 9150151.
↑ Claes K, Machackova E, De Vos M, Poppe B, De Paepe A, Messiaen L (1999). "Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G". Disease Markers. 15 (1–3): 69–73. doi:10.1155/1999/241046. PMC 3851655. PMID 10595255.
↑ Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van 't Veer LJ, Bakker E, van Ommen GJ, Devilee P (1997). "BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients". Nature Genetics. 17 (3): 341–345. doi:10.1038/ng1197-341. PMID 9354803.
↑ Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H (2001). "Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families". European Journal of Cancer. 37 (16): 2082–2090. doi:10.1016/S0959-8049(01)00244-1. PMID 11597388.
↑ Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R (1998). "Evidence of founder mutations in Finnish BRCA1 and BRCA2 families". American Journal of Human Genetics. 62 (6): 1544–1548. doi:10.1086/301880. PMC 1377159. PMID 9585608.
↑ Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kääriäinen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J (2001). "Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population". Genetic Epidemiology. 20 (2): 239–246. doi:10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y. PMID 11180449.
↑ Muller D, Bonaiti-Pellié C, Abecassis J, Stoppa-Lyonnet D, Fricker JP (2004). "BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect". Familial Cancer. 3 (1): 15–20. doi:10.1023/B:FAME.0000026819.44213.df. PMID 15131401.
↑ Tonin PN, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D (1999). "Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history". Clinical Genetics. 55 (5): 318–324. doi:10.1034/j.1399-0004.1999.550504.x. PMID 10422801.
↑ Backe J, Hofferbert S, Skawran B, Dörk T, Stuhrmann M, Karstens JH, Untch M, Meindl A, Burgemeister R, Chang-Claude J, Weber BH (1999). "Frequency of BRCA1 mutation 5382insC in German breast cancer patients". Gynecologic Oncology. 72 (3): 402–406. doi:10.1006/gyno.1998.5270. PMID 10053113.
↑ "Mutation data of the BRCA1 gene". KMDB/MutationView (Keio Mutation Databases). Keio University.
↑ Ladopoulou A, Kroupis C, Konstantopoulou I, Ioannidou-Mouzaka L, Schofield AC, Pantazidis A, Armaou S, Tsiagas I, Lianidou E, Efstathiou E, Tsionou C, Panopoulos C, Mihalatos M, Nasioulas G, Skarlos D, Haites NE, Fountzilas G, Pandis N, Yannoukakos D (2002). "Germ line BRCA1 and BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed". Cancer Letters. 185 (1): 61–70. doi:10.1016/S0304-3835(01)00845-X. PMID 12142080.
↑ Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, Toth J, Devilee P, King MC, Olah E (2000). "Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary". International Journal of Cancer. 86 (5): 737–740. doi:10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1. PMID 10797299.
↑ Baudi F, Quaresima B, Grandinetti C, Cuda G, Faniello C, Tassone P, Barbieri V, Bisegna R, Ricevuto E, Conforti S, Viel A, Marchetti P, Ficorella C, Radice P, Costanzo F, Venuta S (2001). "Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer". Human Mutation. 18 (2): 163–164. doi:10.1002/humu.1167. PMID 11462242.
↑ Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, Fujii T, Nagata I, Ushijima K, Obata K, Suzuki M, Yoshinaga M, Umesaki N, Satoh S, Enomoto T, Motoyama S, Tanaka K (2001). "Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population". Clinical Cancer Research. 7 (10): 3144–3150. PMID 11595708.
↑ Liede A, Jack E, Hegele RA, Narod SA (2002). "A BRCA1 mutation in Native North American families". Human Mutation. 19 (4): 460. doi:10.1002/humu.9027. PMID 11933205.
↑ ^62.0 ^62.1 The Scottish/Northern Irish BRCA1/BRCA2 Consortium (2003). "BRCA1 and BRCA2 mutations in Scotland and Northern Ireland". British Journal of Cancer. 88 (8): 1256–1262. doi:10.1038/sj.bjc.6600840. PMC 2747571. PMID 12698193.
↑ Borg A, Dørum A, Heimdal K, Maehle L, Hovig E, Møller P (1999). "BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations". Disease Markers. 15 (1–3): 79–84. doi:10.1155/1999/278269. PMC 3851406. PMID 10595257.
↑ Heimdal K, Maehle L, Apold J, Pedersen JC, Møller P (2003). "The Norwegian founder mutations in BRCA1: high penetrance confirmed in an incident cancer series and differences observed in the risk of ovarian cancer". European Journal of Cancer. 39 (15): 2205–2213. doi:10.1016/S0959-8049(03)00548-3. PMID 14522380.
↑ Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA (2002). "Contribution of BRCA1 and BRCA2 Mutations to Breast and Ovarian Cancer in Pakistan". American Journal of Human Genetics. 71 (3): 595–606. doi:10.1086/342506. PMC 379195. PMID 12181777.
↑ Górski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, Pluzańska A, Bebenek M, Fischer-Maliszewska L, Grzybowska E, Narod SA, Lubiński J (2000). "Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer". American Journal of Human Genetics. 66 (6): 1963–1968. doi:10.1086/302922. PMC 1378051. PMID 10788334.
↑ Perkowska M, BroZek I, Wysocka B, Haraldsson K, Sandberg T, Johansson U, Sellberg G, Borg A, Limon J (May 2003). "BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland". Hum. Mutat. 21 (5): 553–4. doi:10.1002/humu.9139. PMID 12673801.
↑ Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva RF, Ponder BA (May 1997). "Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia". Am. J. Hum. Genet. 60 (5): 1239–42. PMC 1712436. PMID 9150173.
↑ Liede A, Cohen B, Black DM, Davidson RH, Renwick A, Hoodfar E, Olopade OI, Micek M, Anderson V, De Mey R, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod SA, Steel CM (February 2000). "Evidence of a founder BRCA1 mutation in Scotland". Br. J. Cancer. 82 (3): 705–11. doi:10.1054/bjoc.1999.0984. PMC 2363321. PMID 10682686.
↑ Vega A, Campos B, Bressac-De-Paillerets B, Bond PM, Janin N, Douglas FS, Domènech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, Diez O (June 2001). "The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript". Hum. Mutat. 17 (6): 520–1. doi:10.1002/humu.1136. PMID 11385711.
↑ Campos B, Díez O, Odefrey F, Domènech M, Moncoutier V, Martínez-Ferrandis JI, Osorio A, Balmaña J, Barroso A, Armengod ME, Benítez J, Alonso C, Stoppa-Lyonnet D, Goldgar D, Baiget M (April 2003). "Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain". Hum. Mutat. 21 (4): 452. doi:10.1002/humu.9133. PMID 12655574.
↑ Bergman A, Einbeigi Z, Olofsson U, Taib Z, Wallgren A, Karlsson P, Wahlström J, Martinsson T, Nordling M (October 2001). "The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation". Eur. J. Hum. Genet. 9 (10): 787–93. doi:10.1038/sj.ejhg.5200704. PMID 11781691.
↑ ^73.0 ^73.1 Breast cancer. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/breast/signs-and-symptoms/?region=on#ixzz3xScycfqv Accessed on January 16, 2016

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[Peelen1997-47] 47.0 ^47.1 Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, van der Luijt R, van der Hout AH, Gille JJ, Pals G, Jedema I, Olmer R, van Leeuwen I, Newman B, Plandsoen M, van der Est M, Brink G, Hageman S, Arts PJ, Bakker MM, Devilee P (1997). "A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families". American Journal of Human Genetics. 60 (5): 1041–1049. PMC 1712432. PMID 9150151.

[Claes1999-48] Claes K, Machackova E, De Vos M, Poppe B, De Paepe A, Messiaen L (1999). "Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G". Disease Markers. 15 (1–3): 69–73. doi:10.1155/1999/241046. PMC 3851655. PMID 10595255.

[PetrijBosch-49] Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van 't Veer LJ, Bakker E, van Ommen GJ, Devilee P (1997). "BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients". Nature Genetics. 17 (3): 341–345. doi:10.1038/ng1197-341. PMID 9354803.

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[Huusko-51] Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R (1998). "Evidence of founder mutations in Finnish BRCA1 and BRCA2 families". American Journal of Human Genetics. 62 (6): 1544–1548. doi:10.1086/301880. PMC 1377159. PMID 9585608.

[Paakkonen-52] Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kääriäinen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J (2001). "Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population". Genetic Epidemiology. 20 (2): 239–246. doi:10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y. PMID 11180449.

[Muller-53] Muller D, Bonaiti-Pellié C, Abecassis J, Stoppa-Lyonnet D, Fricker JP (2004). "BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect". Familial Cancer. 3 (1): 15–20. doi:10.1023/B:FAME.0000026819.44213.df. PMID 15131401.

[Tonin1999-54] Tonin PN, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D (1999). "Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history". Clinical Genetics. 55 (5): 318–324. doi:10.1034/j.1399-0004.1999.550504.x. PMID 10422801.

[Backe1999-55] Backe J, Hofferbert S, Skawran B, Dörk T, Stuhrmann M, Karstens JH, Untch M, Meindl A, Burgemeister R, Chang-Claude J, Weber BH (1999). "Frequency of BRCA1 mutation 5382insC in German breast cancer patients". Gynecologic Oncology. 72 (3): 402–406. doi:10.1006/gyno.1998.5270. PMID 10053113.

[urlBrca1-56] "Mutation data of the BRCA1 gene". KMDB/MutationView (Keio Mutation Databases). Keio University.

[Ladopoulou2002-57] Ladopoulou A, Kroupis C, Konstantopoulou I, Ioannidou-Mouzaka L, Schofield AC, Pantazidis A, Armaou S, Tsiagas I, Lianidou E, Efstathiou E, Tsionou C, Panopoulos C, Mihalatos M, Nasioulas G, Skarlos D, Haites NE, Fountzilas G, Pandis N, Yannoukakos D (2002). "Germ line BRCA1 and BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed". Cancer Letters. 185 (1): 61–70. doi:10.1016/S0304-3835(01)00845-X. PMID 12142080.

[VanDerLooij2000-58] Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, Toth J, Devilee P, King MC, Olah E (2000). "Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary". International Journal of Cancer. 86 (5): 737–740. doi:10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1. PMID 10797299.

[Baudi2001-59] Baudi F, Quaresima B, Grandinetti C, Cuda G, Faniello C, Tassone P, Barbieri V, Bisegna R, Ricevuto E, Conforti S, Viel A, Marchetti P, Ficorella C, Radice P, Costanzo F, Venuta S (2001). "Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer". Human Mutation. 18 (2): 163–164. doi:10.1002/humu.1167. PMID 11462242.

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[Borg1999-63] Borg A, Dørum A, Heimdal K, Maehle L, Hovig E, Møller P (1999). "BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations". Disease Markers. 15 (1–3): 79–84. doi:10.1155/1999/278269. PMC 3851406. PMID 10595257.

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[Liede2002-65] Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA (2002). "Contribution of BRCA1 and BRCA2 Mutations to Breast and Ovarian Cancer in Pakistan". American Journal of Human Genetics. 71 (3): 595–606. doi:10.1086/342506. PMC 379195. PMID 12181777.

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[Campos2003-71] Campos B, Díez O, Odefrey F, Domènech M, Moncoutier V, Martínez-Ferrandis JI, Osorio A, Balmaña J, Barroso A, Armengod ME, Benítez J, Alonso C, Stoppa-Lyonnet D, Goldgar D, Baiget M (April 2003). "Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain". Hum. Mutat. 21 (4): 452. doi:10.1002/humu.9133. PMID 12655574.

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[ss-73] 73.0 ^73.1 Breast cancer. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/breast/signs-and-symptoms/?region=on#ixzz3xScycfqv Accessed on January 16, 2016

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@@ Line 5: / Line 5: @@
 ==Overview==
 Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1and 2, HER2), multiple gene panels (i.e. Oncotype DX''')''',  tumor markers (Ki67), and metastatic markers such as serum [[alkaline phosphatase]] as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests ([[Alanine transaminase|alanine aminotransferase]] ([[Alanine transaminase|ALT]]), [[aspartate transaminase]] ([[Aspartate transaminase|AST]]) , bilirubin, [[alkaline phosphatase]]) and markers of kidney function (BUN, creatinine).
-==Blood chemistry==
-Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. <ref name="ss">Breast cancer. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/breast/signs-and-symptoms/?region=on#ixzz3xScycfqv Accessed on January 16, 2016</ref>
-*[[Urea]] ([[blood urea nitrogen]] or [[Blood urea nitrogen|BUN]]) and [[creatinine]] may be measured to check kidney function. Kidney function is checked before chemotherapy is given and may be rechecked during or after treatment.
-*[[Alanine transaminase|Alanine aminotransferase]] ([[Alanine transaminase|ALT]]), [[aspartate transaminase]] ([[Aspartate transaminase|AST]]) and [[alkaline phosphatase]] may be measured to check liver function.
-:*Increased levels could indicate that cancer has spread to the liver.
-*[[Alkaline phosphatase]] can also be used to check for cancer in the bone.
-:*Increased levels could indicate that cancer has spread to the [[bone]].
-:*Tumor markers such as [[Ki-67 (Biology)|'''Ki67''']]
 ==[[BRCA1]]/[[BRCA2]] ==
 Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence.
@@ Line 29: / Line 20: @@
 A protein called [[valosin-containing protein]] (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites.  After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.<ref name="pmid22020440">{{cite journal | vauthors = Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hübscher U, Meyer H, Ramadan K | title = The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks | journal = Nat. Cell Biol. | volume = 13 | issue = 11 | pages = 1376–82 | date = November 2011 | pmid = 22020440 | doi = 10.1038/ncb2367 }}</ref>  BRCA1 interacts with VCP.<ref>{{cite journal | vauthors = Zhang H, Wang Q, Kajino K, Greene MI | title = VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells | journal = DNA Cell Biol | volume = 19 | issue = 5 | pages = 253–263 | year = 2000 | pmid = 10855792 | doi = 10.1089/10445490050021168 }}</ref> BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.<ref name="pmid9788437">{{cite journal | vauthors = Wang Q, Zhang H, Kajino K, Greene MI | title = BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells | journal = Oncogene | volume = 17 | issue = 15 | pages = 1939–48 | date = October 1998 | pmid = 9788437 | doi = 10.1038/sj.onc.1202403 }}</ref>
-BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the [[Mre11-Rad50-Nbs1|MRN]] complex as well as the nuclease activity of Mre11 alone.<ref name=Paull2001>{{cite journal | vauthors = Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M | title = Direct DNA binding by Brca1 | journal = Proceedings of the National Academy of Sciences | volume = 98 | issue = 11 | pages = 6086–6091 | year = 2001 | pmid = 11353843 | pmc = 33426 | doi = 10.1073/pnas.111125998 }}</ref> This may explain a role for BRCA1 to promote lower fidelity DNA repair by [[non-homologous end joining]] (NHEJ).<ref name=Durant2005>{{cite journal | vauthors = Durant ST, Nickoloff JA | title = Good timing in the cell cycle for precise DNA repair by BRCA1 | journal = Cell Cycle | volume = 4 | issue = 9 | pages = 1216–22 | year = 2005 | pmid = 16103751 | doi = 10.4161/cc.4.9.2027 }}</ref> BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.<ref name=Starita2003 /><ref name=Ye2001>{{cite journal | vauthors = Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R | title = BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 911–922 | year = 2001 | pmid = 11739404 | pmc = 2150890 | doi = 10.1083/jcb.200108049 }}</ref>
+BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the [[Mre11-Rad50-Nbs1|MRN]] complex as well as the nuclease activity of Mre11 alone.<ref name="Paull2001">{{cite journal | vauthors = Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M | title = Direct DNA binding by Brca1 | journal = Proceedings of the National Academy of Sciences | volume = 98 | issue = 11 | pages = 6086–6091 | year = 2001 | pmid = 11353843 | pmc = 33426 | doi = 10.1073/pnas.111125998 }}</ref> This may explain a role for BRCA1 to promote lower fidelity DNA repair by [[non-homologous end joining]] (NHEJ).<ref name="Durant2005">{{cite journal | vauthors = Durant ST, Nickoloff JA | title = Good timing in the cell cycle for precise DNA repair by BRCA1 | journal = Cell Cycle | volume = 4 | issue = 9 | pages = 1216–22 | year = 2005 | pmid = 16103751 | doi = 10.4161/cc.4.9.2027 }}</ref> BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.<ref name="Starita2003" /><ref name="Ye2001">{{cite journal | vauthors = Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R | title = BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 911–922 | year = 2001 | pmid = 11739404 | pmc = 2150890 | doi = 10.1083/jcb.200108049 }}</ref>
-[[Formaldehyde]] and [[acetaldehyde]] are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.<ref name="Friedenson_2012">{{cite journal | vauthors = Friedenson B | title = A common environmental carcinogen unduly affects carriers of cancer mutations: carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen | journal = Med. Hypotheses | volume = 77 | issue = 5 | pages = 791–7 | date = November 2011 | pmid = 21839586 | doi = 10.1016/j.mehy.2011.07.039 }}</ref><ref name=Ridpath_2007>{{cite journal | vauthors = Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J | title = Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde | journal = Cancer Res. | volume = 67 | issue = 23 | pages = 11117–22 | date = December 2007 | pmid = 18056434 | doi = 10.1158/0008-5472.CAN-07-3028 }}</ref>
+[[Formaldehyde]] and [[acetaldehyde]] are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.<ref name="Friedenson_2012">{{cite journal | vauthors = Friedenson B | title = A common environmental carcinogen unduly affects carriers of cancer mutations: carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen | journal = Med. Hypotheses | volume = 77 | issue = 5 | pages = 791–7 | date = November 2011 | pmid = 21839586 | doi = 10.1016/j.mehy.2011.07.039 }}</ref><ref name="Ridpath_2007">{{cite journal | vauthors = Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J | title = Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde | journal = Cancer Res. | volume = 67 | issue = 23 | pages = 11117–22 | date = December 2007 | pmid = 18056434 | doi = 10.1158/0008-5472.CAN-07-3028 }}</ref>
 This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was [[hypomorphic]].<ref>{{cite journal | vauthors = Prakash R, Zhang Y, Feng W, Jasin M | title = Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 4 | pages = a016600 | date = April 2015 | pmid = 25833843 | pmc = 4382744 | doi = 10.1101/cshperspect.a016600 }}</ref>
@@ Line 47: / Line 38: @@
 BRCA1 mRNA [[three prime untranslated region|3' UTR]] can be bound by an [[miRNA]], [[Mir-17 microRNA precursor family|Mir-17 microRNA]]. It has been suggested that variations in this miRNA along with [[Mir-30 microRNA precursor|Mir-30 microRNA]] could confer susceptibility to breast cancer.<ref>{{cite journal | vauthors = Shen J, Ambrosone CB, Zhao H | title = Novel genetic variants in microRNA genes and familial breast cancer | journal = Int. J. Cancer | volume = 124 | issue = 5 | pages = 1178–82 | date = March 2009 | pmid = 19048628 | doi = 10.1002/ijc.24008 }}</ref>
-In addition to breast cancer, mutations in the ''BRCA1'' gene also increase the risk of [[ovarian cancer|ovarian]] and [[prostate cancer]]s. Moreover, precancerous lesions ([[dysplasia]]) within the [[Fallopian tube]] have been linked to ''BRCA1'' gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.<ref name="pmid17683622"/>
+In addition to breast cancer, mutations in the ''BRCA1'' gene also increase the risk of [[ovarian cancer|ovarian]] and [[prostate cancer]]s. Moreover, precancerous lesions ([[dysplasia]]) within the [[Fallopian tube]] have been linked to ''BRCA1'' gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.<ref name="pmid17683622" />
-Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.<ref name ="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Mol Med | volume = 18 | issue = 9 | pages = 1327–37 | year = 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref>
+Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Mol Med | volume = 18 | issue = 9 | pages = 1327–37 | year = 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref>
 =====Low expression of ''BRCA1'' in breast and ovarian cancers=====
-BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.<ref name="pmid9988281">{{cite journal |vauthors=Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ |title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas |journal=Nat. Genet. |volume=21 |issue=2 |pages=236–40 |year=1999 |pmid=9988281 |doi=10.1038/6029 |url=}}</ref>  It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.  In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.<ref name="pmid12559046">{{cite journal |vauthors=Mueller CR, Roskelley CD |title=Regulation of BRCA1 expression and its relationship to sporadic breast cancer |journal=Breast Cancer Res. |volume=5 |issue=1 |pages=45–52 |year=2003 |pmid=12559046 |pmc=154136 |doi= 10.1186/bcr557}}</ref>  Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.<ref name=Jacinto>{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |year=2007 |pmid=17412712 |doi=10.1093/mutage/gem009 |url=}}</ref>  Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.<ref name=Jacinto />
+BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.<ref name="pmid9988281">{{cite journal |vauthors=Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ |title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas |journal=Nat. Genet. |volume=21 |issue=2 |pages=236–40 |year=1999 |pmid=9988281 |doi=10.1038/6029 |url=}}</ref>  It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.  In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.<ref name="pmid12559046">{{cite journal |vauthors=Mueller CR, Roskelley CD |title=Regulation of BRCA1 expression and its relationship to sporadic breast cancer |journal=Breast Cancer Res. |volume=5 |issue=1 |pages=45–52 |year=2003 |pmid=12559046 |pmc=154136 |doi= 10.1186/bcr557}}</ref>  Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.<ref name="Jacinto">{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |year=2007 |pmid=17412712 |doi=10.1093/mutage/gem009 |url=}}</ref>  Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.<ref name="Jacinto" />
-Similarly, BRCA1 expression is low in the majority (55%) of sporadic [[Ovarian cancer#Epithelial carcinoma|epithelial ovarian cancers (EOCs)]] where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.<ref name=Sun>{{cite journal |vauthors=Sun C, Li N, Yang Z, Zhou B, He Y, Weng D, Fang Y, Wu P, Chen P, Yang X, Ma D, Zhou J, Chen G |title=miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition |journal=J. Natl. Cancer Inst. |volume=105 |issue=22 |pages=1750–8 |year=2013 |pmid=24168967 |doi=10.1093/jnci/djt302 |url=}}</ref>  In [[Ovarian cancer#Serous carcinoma|serous ovarian carcinomas]], a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.<ref name="pmid22790015">{{cite journal |vauthors=McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ |title=Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1644–53 |year=2012 |pmid=22790015 |doi=10.1038/modpathol.2012.118 |url=}}</ref>  Bowtell<ref name="pmid20944665">{{cite journal |vauthors=Bowtell DD |title=The genesis and evolution of high-grade serous ovarian cancer |journal=Nat. Rev. Cancer |volume=10 |issue=11 |pages=803–8 |year=2010 |pmid=20944665 |doi=10.1038/nrc2946 |url=}}</ref> reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.  In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.  Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
+Similarly, BRCA1 expression is low in the majority (55%) of sporadic [[Ovarian cancer#Epithelial carcinoma|epithelial ovarian cancers (EOCs)]] where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.<ref name="Sun">{{cite journal |vauthors=Sun C, Li N, Yang Z, Zhou B, He Y, Weng D, Fang Y, Wu P, Chen P, Yang X, Ma D, Zhou J, Chen G |title=miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition |journal=J. Natl. Cancer Inst. |volume=105 |issue=22 |pages=1750–8 |year=2013 |pmid=24168967 |doi=10.1093/jnci/djt302 |url=}}</ref>  In [[Ovarian cancer#Serous carcinoma|serous ovarian carcinomas]], a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.<ref name="pmid22790015">{{cite journal |vauthors=McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ |title=Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1644–53 |year=2012 |pmid=22790015 |doi=10.1038/modpathol.2012.118 |url=}}</ref>  Bowtell<ref name="pmid20944665">{{cite journal |vauthors=Bowtell DD |title=The genesis and evolution of high-grade serous ovarian cancer |journal=Nat. Rev. Cancer |volume=10 |issue=11 |pages=803–8 |year=2010 |pmid=20944665 |doi=10.1038/nrc2946 |url=}}</ref> reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.  In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.  Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
 =====Mutation of ''BRCA1'' in breast and ovarian cancer=====
@@ Line 62: / Line 53: @@
 =====''BRCA1'' promoter hypermethylation in breast and ovarian cancer=====
-''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.<ref name="pmid10749912">{{cite journal |vauthors=Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG|authorlink13=Stephen B. Baylin|authorlink14=James G. Herman |title=Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors |journal=J. Natl. Cancer Inst. |volume=92 |issue=7 |pages=564–9 |year=2000 |pmid=10749912 |doi= 10.1093/jnci/92.7.564|url=}}</ref>  Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases.<ref name=Sun />
+''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.<ref name="pmid10749912">{{cite journal |vauthors=Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG|authorlink13=Stephen B. Baylin|authorlink14=James G. Herman |title=Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors |journal=J. Natl. Cancer Inst. |volume=92 |issue=7 |pages=564–9 |year=2000 |pmid=10749912 |doi= 10.1093/jnci/92.7.564|url=}}</ref>  Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases.<ref name="Sun" />
 Thus, while BRCA1 expression is low in these cancers, ''BRCA1'' promoter methylation is only a minor cause of reduced expression.
 =====MicroRNA repression of BRCA1 in breast cancers=====
-There are a number of specific [[MicroRNA#DNA repair and cancer|microRNAs]], when overexpressed, that directly reduce expression of specific DNA repair proteins (see [[MicroRNA#DNA repair and cancer|MicroRNA section DNA repair and cancer]])  In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.<ref name=Moskwa>{{cite journal |vauthors=Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D |title=miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |journal=Mol. Cell |volume=41 |issue=2 |pages=210–20 |year=2011 |pmid=21195000 |pmc=3249932 |doi=10.1016/j.molcel.2010.12.005 |url=}}</ref>  Breast cancers can be [[Breast cancer classification|classified]] based on receptor status or histology, with [[triple-negative breast cancer]] (15%–25% of breast cancers), [[Breast cancer#HER2 and cancer|HER2+]] (15%–30% of breast cancers), [[Estrogen receptor#Cancer|ER+]]/[[Progesterone receptor|PR+]] (about 70% of breast cancers), and [[Invasive lobular carcinoma]] (about 5%–10% of invasive breast cancer).  All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.<ref name="pmid23249749">{{cite journal |vauthors=Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM |title=MicroRNA-182-5p targets a network of genes involved in DNA repair |journal=RNA |volume=19 |issue=2 |pages=230–42 |year=2013 |pmid=23249749 |pmc=3543090 |doi=10.1261/rna.034926.112 |url=}}</ref>  In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.<ref name=Moskwa /> Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.
+There are a number of specific [[MicroRNA#DNA repair and cancer|microRNAs]], when overexpressed, that directly reduce expression of specific DNA repair proteins (see [[MicroRNA#DNA repair and cancer|MicroRNA section DNA repair and cancer]])  In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.<ref name="Moskwa">{{cite journal |vauthors=Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D |title=miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |journal=Mol. Cell |volume=41 |issue=2 |pages=210–20 |year=2011 |pmid=21195000 |pmc=3249932 |doi=10.1016/j.molcel.2010.12.005 |url=}}</ref>  Breast cancers can be [[Breast cancer classification|classified]] based on receptor status or histology, with [[triple-negative breast cancer]] (15%–25% of breast cancers), [[Breast cancer#HER2 and cancer|HER2+]] (15%–30% of breast cancers), [[Estrogen receptor#Cancer|ER+]]/[[Progesterone receptor|PR+]] (about 70% of breast cancers), and [[Invasive lobular carcinoma]] (about 5%–10% of invasive breast cancer).  All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.<ref name="pmid23249749">{{cite journal |vauthors=Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM |title=MicroRNA-182-5p targets a network of genes involved in DNA repair |journal=RNA |volume=19 |issue=2 |pages=230–42 |year=2013 |pmid=23249749 |pmc=3543090 |doi=10.1261/rna.034926.112 |url=}}</ref>  In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.<ref name="Moskwa" /> Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.
 In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.  These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.<ref name="pmid21472990">{{cite journal |vauthors=Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S |title=Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers |journal=EMBO Mol Med |volume=3 |issue=5 |pages=279–90 |year=2011 |pmid=21472990 |pmc=3377076 |doi=10.1002/emmm.201100136 |url=}}</ref>  Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
-======MicroRNA repression of BRCA1 in ovarian cancers=====
+=====MicroRNA repression of BRCA1 in ovarian cancers=====
-In both [[Ovarian cancer#Pathophysiology|serous tubal intraepithelial carcinoma]] (the precursor lesion to [[Ovarian cancer#Pathophysiology|high grade serous ovarian carcinoma (HG-SOC)]]), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.<ref name=Liu>{{cite journal |vauthors=Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ |title=MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma |journal=J. Pathol. |volume=228 |issue=2 |pages=204–15 |year=2012 |pmid=22322863 |doi=10.1002/path.4000 |url=}}</ref>  In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).<ref name=Liu />  Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.
+In both [[Ovarian cancer#Pathophysiology|serous tubal intraepithelial carcinoma]] (the precursor lesion to [[Ovarian cancer#Pathophysiology|high grade serous ovarian carcinoma (HG-SOC)]]), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.<ref name="Liu">{{cite journal |vauthors=Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ |title=MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma |journal=J. Pathol. |volume=228 |issue=2 |pages=204–15 |year=2012 |pmid=22322863 |doi=10.1002/path.4000 |url=}}</ref>  In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).<ref name="Liu" />  Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.
-Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.<ref name=Sun />  Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,<ref name=Sun /> so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
+Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.<ref name="Sun" />  Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,<ref name="Sun" /> so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
 {{Dynamic list}}
-{|  class="wikitable"
+{| class="wikitable"
 |-
 ! Population or subgroup !! BRCA1 mutation(s)<ref name="denDunnen2000">{{cite journal | vauthors = den Dunnen JT, Antonarakis SE | title = Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion | journal = Human Mutation | volume = 15 | issue = 1 | pages = 7–12 | year = 2000 | pmid = 10612815 | doi = 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N }}</ref> !! Reference(s)
@@ Line 86: / Line 77: @@
 | Afrikaners || E881X  ||  <ref name="Reeves2004">{{cite journal | vauthors = Reeves MD, Yawitch TM, van der Merwe NC, van den Berg HJ, Dreyer G, van Rensburg EJ | title = BRCA1 mutations in South African breast and/or ovarian cancer families: evidence of a novel founder mutation in Afrikaner families | journal = Int. J. Cancer | volume = 110 | issue = 5 | pages = 677–82 | date = July 2004 | pmid = 15146556 | doi = 10.1002/ijc.20186 }}</ref>
 |-
-| Ashkenazi Jewish || 185delAG, 188del11, 5382insC  ||  <ref name="Struewing1995"/><ref name="Tonin1995"/>
+| Ashkenazi Jewish || 185delAG, 188del11, 5382insC  ||  <ref name="Struewing1995" /><ref name="Tonin1995" />
 |-
 | Austrians || 2795delA, C61G, 5382insC, Q1806stop || <ref name="Wagner1998">{{cite journal | vauthors = Wagner TM, Möslinger RA, Muhr D, Langbauer G, Hirtenlehner K, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Ropp E, Kubista E, Amirimani B, Helbich T, Becherer A, Scheiner O, Breiteneder H, Borg A, Devilee P, Oefner P, Zielinski C | title = BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics | journal = International Journal of Cancer | volume = 77 | issue = 3 | pages = 354–360 | year = 1998 | pmid = 9663595 | doi = 10.1002/(SICI)1097-0215(19980729)77:3<354::AID-IJC8>3.0.CO;2-N }}</ref>
@@ Line 92: / Line 83: @@
 | Belgians || 2804delAA, IVS5+3A>G || <ref name="Peelen1997">{{cite journal | vauthors = Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, van der Luijt R, van der Hout AH, Gille JJ, Pals G, Jedema I, Olmer R, van Leeuwen I, Newman B, Plandsoen M, van der Est M, Brink G, Hageman S, Arts PJ, Bakker MM, Devilee P | title = A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1041–1049 | year = 1997 | pmid = 9150151 | pmc = 1712432 }}</ref><ref name="Claes1999">{{cite journal | vauthors = Claes K, Machackova E, De Vos M, Poppe B, De Paepe A, Messiaen L | title = Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G | journal = Disease Markers | volume = 15 | issue = 1–3 | pages = 69–73 | year = 1999 | pmid = 10595255 | pmc = 3851655 | doi = 10.1155/1999/241046 }}</ref>
 |-
-| Dutch || Exon 2 deletion, exon 13 deletion, 2804delAA  || <ref name="Peelen1997"/><ref name="PetrijBosch">{{cite journal | vauthors = Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van 't Veer LJ, Bakker E, van Ommen GJ, Devilee P | title = BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients | journal = Nature Genetics | volume = 17 | issue = 3 | pages = 341–345 | year = 1997 | pmid = 9354803 | doi = 10.1038/ng1197-341 }}</ref><ref name="Verhoog">{{cite journal | vauthors = Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H | title = Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families | journal = European Journal of Cancer | volume = 37 | issue = 16 | pages = 2082–2090 | year = 2001 | pmid = 11597388 | doi = 10.1016/S0959-8049(01)00244-1 }}</ref>
+| Dutch || Exon 2 deletion, exon 13 deletion, 2804delAA  || <ref name="Peelen1997" /><ref name="PetrijBosch">{{cite journal | vauthors = Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van 't Veer LJ, Bakker E, van Ommen GJ, Devilee P | title = BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients | journal = Nature Genetics | volume = 17 | issue = 3 | pages = 341–345 | year = 1997 | pmid = 9354803 | doi = 10.1038/ng1197-341 }}</ref><ref name="Verhoog">{{cite journal | vauthors = Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H | title = Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families | journal = European Journal of Cancer | volume = 37 | issue = 16 | pages = 2082–2090 | year = 2001 | pmid = 11597388 | doi = 10.1016/S0959-8049(01)00244-1 }}</ref>
 |-
 | Finns || 3745delT, IVS11-2A>G  || <ref name="Huusko">{{cite journal | vauthors = Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R | title = Evidence of founder mutations in Finnish BRCA1 and BRCA2 families | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1544–1548 | year = 1998 | pmid = 9585608 | pmc = 1377159 | doi = 10.1086/301880 }}</ref><ref name="Paakkonen">{{cite journal | vauthors = Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kääriäinen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J | title = Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population | journal = Genetic Epidemiology | volume = 20 | issue = 2 | pages = 239–246 | year = 2001 | pmid = 11180449 | doi = 10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y }}</ref>
@@ Line 122: / Line 113: @@
 | Russians || 5382insC, 4153delA  || <ref name="Gayther1997">{{cite journal | vauthors = Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva RF, Ponder BA | title = Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia | journal = Am. J. Hum. Genet. | volume = 60 | issue = 5 | pages = 1239–42 | date = May 1997 | pmid = 9150173 | pmc = 1712436 | doi = }}</ref>
 |-
-| Scottish || 2800delAA  ||  <ref name="TSNI2003"/><ref name="Liede2000">{{cite journal | vauthors = Liede A, Cohen B, Black DM, Davidson RH, Renwick A, Hoodfar E, Olopade OI, Micek M, Anderson V, De Mey R, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod SA, Steel CM | title = Evidence of a founder BRCA1 mutation in Scotland | journal = Br. J. Cancer | volume = 82 | issue = 3 | pages = 705–11 | date = February 2000 | pmid = 10682686 | pmc = 2363321 | doi = 10.1054/bjoc.1999.0984 }}</ref>
+| Scottish || 2800delAA  ||  <ref name="TSNI2003" /><ref name="Liede2000">{{cite journal | vauthors = Liede A, Cohen B, Black DM, Davidson RH, Renwick A, Hoodfar E, Olopade OI, Micek M, Anderson V, De Mey R, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod SA, Steel CM | title = Evidence of a founder BRCA1 mutation in Scotland | journal = Br. J. Cancer | volume = 82 | issue = 3 | pages = 705–11 | date = February 2000 | pmid = 10682686 | pmc = 2363321 | doi = 10.1054/bjoc.1999.0984 }}</ref>
 |-
 | Spanish || R71G  ||  <ref name="Vega2001">{{cite journal | vauthors = Vega A, Campos B, Bressac-De-Paillerets B, Bond PM, Janin N, Douglas FS, Domènech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, Diez O | title = The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript | journal = Hum. Mutat. | volume = 17 | issue = 6 | pages = 520–1 | date = June 2001 | pmid = 11385711 | doi = 10.1002/humu.1136 }}</ref><ref name="Campos2003">{{cite journal | vauthors = Campos B, Díez O, Odefrey F, Domènech M, Moncoutier V, Martínez-Ferrandis JI, Osorio A, Balmaña J, Barroso A, Armengod ME, Benítez J, Alonso C, Stoppa-Lyonnet D, Goldgar D, Baiget M | title = Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain | journal = Hum. Mutat. | volume = 21 | issue = 4 | page = 452 | date = April 2003 | pmid = 12655574 | doi = 10.1002/humu.9133 }}</ref>
 |-
-| Swedish || Q563X, 3171ins5, 1201del11, 2594delC  || <ref name="Neuhausen2000"/><ref name="Bergman2001">{{cite journal | vauthors = Bergman A, Einbeigi Z, Olofsson U, Taib Z, Wallgren A, Karlsson P, Wahlström J, Martinsson T, Nordling M | title = The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation | journal = Eur. J. Hum. Genet. | volume = 9 | issue = 10 | pages = 787–93 | date = October 2001 | pmid = 11781691 | doi = 10.1038/sj.ejhg.5200704 }}</ref>
+| Swedish || Q563X, 3171ins5, 1201del11, 2594delC  || <ref name="Neuhausen2000" /><ref name="Bergman2001">{{cite journal | vauthors = Bergman A, Einbeigi Z, Olofsson U, Taib Z, Wallgren A, Karlsson P, Wahlström J, Martinsson T, Nordling M | title = The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation | journal = Eur. J. Hum. Genet. | volume = 9 | issue = 10 | pages = 787–93 | date = October 2001 | pmid = 11781691 | doi = 10.1038/sj.ejhg.5200704 }}</ref>
 |}
+BRCA2
 ==HER2==
@@ Line 135: / Line 127: @@
 * '''Oncotype DX'''®
 * '''MammaPrint'''®
+==Blood chemistry==
+Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. <ref name="ss" />
+*[[Urea]] ([[blood urea nitrogen]] or [[Blood urea nitrogen|BUN]]) and [[creatinine]] may be measured to check kidney function. Kidney function is checked before chemotherapy is given and may be rechecked during or after treatment.
+*[[Alanine transaminase|Alanine aminotransferase]] ([[Alanine transaminase|ALT]]), [[aspartate transaminase]] ([[Aspartate transaminase|AST]]) and [[alkaline phosphatase]] may be measured to check liver function.
+:*Increased levels could indicate that cancer has spread to the liver.
+*[[Alkaline phosphatase]] can also be used to check for cancer in the bone.
+:*Increased levels could indicate that cancer has spread to the [[bone]].
+:*Tumor markers such as [[Ki-67 (Biology)|'''Ki67''']]
 ==References==