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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>
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>
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 [[mutation]]s 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.<ref name="urlGenetics">{{cite web | url = http://www.breastcancer.org/risk/factors/genetics | title = Genetics | date = 2012-09-17 | work = | publisher = Breastcancer.org | accessdate = }}</ref>
These mutations can be changes in one or a small number of DNA [[base pair]]s (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.{{citation needed|date=January 2016}}
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.<ref name="pmid15832305">{{cite journal | vauthors = Mazoyer S | title = Genomic rearrangements in the BRCA1 and BRCA2 genes | journal = Hum. Mutat. | volume = 25 | issue = 5 | pages = 415–22 | date = May 2005 | pmid = 15832305 | doi = 10.1002/humu.20169 }}</ref> Other methods have been proposed: traditional [[quantitative PCR]],<ref name="pmid14984472">{{cite journal | vauthors = Barrois M, Bièche I, Mazoyer S, Champème MH, Bressac-de Paillerets B, Lidereau R | title = Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families | journal = Clin. Genet. | volume = 65 | issue = 2 | pages = 131–6 | date = February 2004 | pmid = 14984472 | doi = 10.1111/j.0009-9163.2004.00200.x }}</ref> [[Multiplex Ligation-dependent Probe Amplification]] (MLPA),<ref name="pmid12670888">{{cite journal | vauthors = Hogervorst FB, Nederlof PM, Gille JJ, McElgunn CJ, Grippeling M, Pruntel R, Regnerus R, van Welsem T, van Spaendonk R, Menko FH, Kluijt I, Dommering C, Verhoef S, Schouten JP, van't Veer LJ, Pals G | title = Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method | journal = Cancer Res. | volume = 63 | issue = 7 | pages = 1449–53 | date = April 2003 | pmid = 12670888 | doi = }}</ref> and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).<ref name="pmid12203994">{{cite journal | vauthors = Casilli F, Di Rocco ZC, Gad S, Tournier I, Stoppa-Lyonnet D, Frebourg T, Tosi M | title = Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments | journal = Hum. Mutat. | volume = 20 | issue = 3 | pages = 218–26 | date = September 2002 | pmid = 12203994 | doi = 10.1002/humu.10108 }}</ref> 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).<ref name="pmid17718857">{{cite journal | vauthors = Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F, Nogues C, Bieche I, Lidereau R | title = High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1 | journal = Clin. Genet. | volume = 72 | issue = 3 | pages = 199–207 | date = September 2007 | pmid = 17718857 | doi = 10.1111/j.1399-0004.2007.00849.x }}</ref>
Some results suggest that [[methylation|hypermethylation]] of the BRCA1 [[Promoter (biology)|promoter]], which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.<ref name="pmid18567944">{{cite journal | vauthors = Tapia T, Smalley SV, Kohen P, Muñoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P | title = Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors | journal = Epigenetics | volume = 3 | issue = 1 | pages = 157–63 | year = 2008 | pmid = 18567944 | doi = 10.1186/bcr1858 }}</ref>
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|date=January 2016}}
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"/>
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 />
 
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=====
Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.<ref name="pmid9653432">{{cite journal |vauthors=Brody LC, Biesecker BB |title=Breast cancer susceptibility genes. BRCA1 and BRCA2 |journal=Medicine (Baltimore) |volume=77 |issue=3 |pages=208–26 |year=1998 |pmid=9653432 |doi= 10.1097/00005792-199805000-00006|url=}}</ref>  Similarly, ''BRCA1'' mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).<ref name="pmid24240112">{{cite journal |vauthors=Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM |title=Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas |journal=Clin. Cancer Res. |volume=20 |issue=3 |pages=764–75 |year=2014 |pmid=24240112 |pmc=3944197 |doi=10.1158/1078-0432.CCR-13-2287 |url=}}</ref>
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'' [[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.
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=====
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.


==HER2==
==HER2==

Revision as of 14:16, 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]

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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).

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. [1]

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

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).[2] BRCA1 orthologs have been identified in most vertebrates for which complete genome data are available [3].

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,[4] 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.[5]

In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.[6] 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.[7] MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.[8]

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.[9] BRCA1 interacts with VCP.[10] BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.[11]

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.[12] This may explain a role for BRCA1 to promote lower fidelity DNA repair by non-homologous end joining (NHEJ).[13] 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.[14][15]

Formaldehyde and acetaldehyde are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.[16][17]

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.[18]

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.[19]

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.[20] Other methods have been proposed: traditional quantitative PCR,[21] Multiplex Ligation-dependent Probe Amplification (MLPA),[22] and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).[23] 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).[24]

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.[25]

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.[26]

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.[27]

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.[28]

Low expression of BRCA1 in breast and ovarian cancers

BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.[29] 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.[30] 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.[31] 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.[31]

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.[32] In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.[33] Bowtell[34] 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.[35] Similarly, BRCA1 mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).[36]

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.[37] Similarly, BRCA1 promoter hypermethylation was present in only 5% to 15% of EOC cases.[32]

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.[38] 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.[39] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.[38] 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.[40] 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.[41] In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).[41] 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.[32] 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,[32] so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.

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.[1]
  • HER2 status testing is done to find out the amount of HER2 produced by a breast tumor.

Multiple gene panels

  • Oncotype DX®
  • MammaPrint®

References

  1. ↑ 1.0 1.1 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
  2. ↑ National Center for Biotechnology Information, U.S. National Library of Medicine EntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)
  3. ↑ "BRCA1 gene tree". Ensembl.
  4. ↑ Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA (2014). "Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype". Cancer Discov. 5 (2): 135–42. doi:10.1158/2159-8290.CD-14-1156. PMC 4320660. PMID 25472942.
  5. ↑ Kimball's Biologh Pages
  6. ↑ Boulton SJ (November 2006). "Cellular functions of the BRCA tumour-suppressor proteins". Biochem. Soc. Trans. 34 (Pt 5): 633–45. doi:10.1042/BST0340633. PMID 17052168.
  7. ↑ Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI (August 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene. 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787.
  8. ↑ Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP, Waisfisz Q, Rottenberg S, Boven E, Jonkers J, Jimenez CR (July 2012). "Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer". Mol. Cell. Proteomics. 11 (7): M111.013334. doi:10.1074/mcp.M111.013334. PMC 3394939. PMID 22366898.
  9. ↑ Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hübscher U, Meyer H, Ramadan K (November 2011). "The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks". Nat. Cell Biol. 13 (11): 1376–82. doi:10.1038/ncb2367. PMID 22020440.
  10. ↑ Zhang H, Wang Q, Kajino K, Greene MI (2000). "VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells". DNA Cell Biol. 19 (5): 253–263. doi:10.1089/10445490050021168. PMID 10855792.
  11. ↑ Wang Q, Zhang H, Kajino K, Greene MI (October 1998). "BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells". Oncogene. 17 (15): 1939–48. doi:10.1038/sj.onc.1202403. PMID 9788437.
  12. ↑ Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M (2001). "Direct DNA binding by Brca1". Proceedings of the National Academy of Sciences. 98 (11): 6086–6091. doi:10.1073/pnas.111125998. PMC 33426. PMID 11353843.
  13. ↑ Durant ST, Nickoloff JA (2005). "Good timing in the cell cycle for precise DNA repair by BRCA1". Cell Cycle. 4 (9): 1216–22. doi:10.4161/cc.4.9.2027. PMID 16103751.
  14. ↑
  15. ↑ Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R (2001). "BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations". The Journal of Cell Biology. 155 (6): 911–922. doi:10.1083/jcb.200108049. PMC 2150890. PMID 11739404.
  16. ↑ Friedenson B (November 2011). "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". Med. Hypotheses. 77 (5): 791–7. doi:10.1016/j.mehy.2011.07.039. PMID 21839586.
  17. ↑ 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 (December 2007). "Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde". Cancer Res. 67 (23): 11117–22. doi:10.1158/0008-5472.CAN-07-3028. PMID 18056434.
  18. ↑ Prakash R, Zhang Y, Feng W, Jasin M (April 2015). "Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins". Cold Spring Harbor Perspectives in Biology. 7 (4): a016600. doi:10.1101/cshperspect.a016600. PMC 4382744. PMID 25833843.
  19. ↑ "Genetics". Breastcancer.org. 2012-09-17.
  20. ↑ Mazoyer S (May 2005). "Genomic rearrangements in the BRCA1 and BRCA2 genes". Hum. Mutat. 25 (5): 415–22. doi:10.1002/humu.20169. PMID 15832305.
  21. ↑ Barrois M, Bièche I, Mazoyer S, Champème MH, Bressac-de Paillerets B, Lidereau R (February 2004). "Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families". Clin. Genet. 65 (2): 131–6. doi:10.1111/j.0009-9163.2004.00200.x. PMID 14984472.
  22. ↑ Hogervorst FB, Nederlof PM, Gille JJ, McElgunn CJ, Grippeling M, Pruntel R, Regnerus R, van Welsem T, van Spaendonk R, Menko FH, Kluijt I, Dommering C, Verhoef S, Schouten JP, van't Veer LJ, Pals G (April 2003). "Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method". Cancer Res. 63 (7): 1449–53. PMID 12670888.
  23. ↑ Casilli F, Di Rocco ZC, Gad S, Tournier I, Stoppa-Lyonnet D, Frebourg T, Tosi M (September 2002). "Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments". Hum. Mutat. 20 (3): 218–26. doi:10.1002/humu.10108. PMID 12203994.
  24. ↑ Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F, Nogues C, Bieche I, Lidereau R (September 2007). "High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1". Clin. Genet. 72 (3): 199–207. doi:10.1111/j.1399-0004.2007.00849.x. PMID 17718857.
  25. ↑ Tapia T, Smalley SV, Kohen P, Muñoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P (2008). "Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors". Epigenetics. 3 (1): 157–63. doi:10.1186/bcr1858. PMID 18567944.
  26. ↑ Shen J, Ambrosone CB, Zhao H (March 2009). "Novel genetic variants in microRNA genes and familial breast cancer". Int. J. Cancer. 124 (5): 1178–82. doi:10.1002/ijc.24008. PMID 19048628.
  27. ↑
  28. ↑ Levin B, Lech D, Friedenson B (2012). "Evidence that BRCA1- or BRCA2-associated cancers are not inevitable". Mol Med. 18 (9): 1327–37. doi:10.2119/molmed.2012.00280. PMC 3521784. PMID 22972572.
  29. ↑ 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 (1999). "Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas". Nat. Genet. 21 (2): 236–40. doi:10.1038/6029. PMID 9988281.
  30. ↑ Mueller CR, Roskelley CD (2003). "Regulation of BRCA1 expression and its relationship to sporadic breast cancer". Breast Cancer Res. 5 (1): 45–52. doi:10.1186/bcr557. PMC 154136. PMID 12559046.
  31. ↑ 31.0 31.1 Jacinto FV, Esteller M (2007). "Mutator pathways unleashed by epigenetic silencing in human cancer". Mutagenesis. 22 (4): 247–53. doi:10.1093/mutage/gem009. PMID 17412712.
  32. ↑ 32.0 32.1 32.2 32.3 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 (2013). "miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition". J. Natl. Cancer Inst. 105 (22): 1750–8. doi:10.1093/jnci/djt302. PMID 24168967.
  33. ↑ McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ (2012). "Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma". Mod. Pathol. 25 (12): 1644–53. doi:10.1038/modpathol.2012.118. PMID 22790015.
  34. ↑ Bowtell DD (2010). "The genesis and evolution of high-grade serous ovarian cancer". Nat. Rev. Cancer. 10 (11): 803–8. doi:10.1038/nrc2946. PMID 20944665.
  35. ↑ Brody LC, Biesecker BB (1998). "Breast cancer susceptibility genes. BRCA1 and BRCA2". Medicine (Baltimore). 77 (3): 208–26. doi:10.1097/00005792-199805000-00006. PMID 9653432.
  36. ↑ Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM (2014). "Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas". Clin. Cancer Res. 20 (3): 764–75. doi:10.1158/1078-0432.CCR-13-2287. PMC 3944197. PMID 24240112.
  37. ↑ 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 (2000). "Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors". J. Natl. Cancer Inst. 92 (7): 564–9. doi:10.1093/jnci/92.7.564. PMID 10749912.
  38. ↑ 38.0 38.1 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 (2011). "miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors". Mol. Cell. 41 (2): 210–20. doi:10.1016/j.molcel.2010.12.005. PMC 3249932. PMID 21195000.
  39. ↑ 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 (2013). "MicroRNA-182-5p targets a network of genes involved in DNA repair". RNA. 19 (2): 230–42. doi:10.1261/rna.034926.112. PMC 3543090. PMID 23249749.
  40. ↑ Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S (2011). "Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers". EMBO Mol Med. 3 (5): 279–90. doi:10.1002/emmm.201100136. PMC 3377076. PMID 21472990.
  41. ↑ 41.0 41.1 Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ (2012). "MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma". J. Pathol. 228 (2): 204–15. doi:10.1002/path.4000. PMID 22322863.

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