Breast cancer laboratory tests: Difference between revisions
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Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence. | Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence. | ||
BRCA1 | ===BRCA1=== | ||
The human ''BRCA1'' gene is located on the long (q) arm of [[chromosome 17 (human)|chromosome 17]] at region 2 band 1, from [[base pair]] 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) [http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&singleSearch=knownCanonical&position=BRCA1 (map)].<ref>National Center for Biotechnology Information, U.S. National Library of Medicine [https://www.ncbi.nlm.nih.gov/gene/672 EntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)]</ref> ''BRCA1'' [[orthologs]] have been identified in most [[vertebrate]]s for which complete genome data are available <ref name="Ensembl">{{cite web |title=BRCA1 gene tree |url=http://www.ensembl.org/Multi/GeneTree/Image?gt=ENSGT00440000034289 |publisher=Ensembl}}</ref>. | |||
====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|Fanconi Anemia]], Complementation Group S,<ref name="pmid25472942">{{cite journal |vauthors=Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA | title = Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype | journal = Cancer Discov | volume = 5| issue = 2| pages = 135–42| year = 2014 | pmid = 25472942 | doi = 10.1158/2159-8290.CD-14-1156 | pmc=4320660}}</ref> 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|homology-directed repair]], where the repair proteins copy the identical sequence from the intact [[sister chromatid]].<ref>[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html#DSBs Kimball's Biologh Pages]</ref> | |||
In the nucleus of many types of normal cells, the BRCA1 protein interacts with [[RAD51]] during repair of DNA double-strand breaks.<ref name="pmid17052168">{{cite journal | vauthors = Boulton SJ | title = Cellular functions of the BRCA tumour-suppressor proteins | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 5 | pages = 633–45 | date = November 2006 | pmid = 17052168 | doi = 10.1042/BST0340633 }}</ref> These breaks can be caused by natural radiation or other exposures, but also occur when [[chromosome]]s 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|date=January 2016}} | |||
BRCA1 is also involved in another type of DNA repair, termed mismatch repair. BRCA1 interacts with the DNA mismatch repair protein MSH2.<ref name="pmid11498787">{{cite journal | vauthors = Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI | title = Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1 | journal = Oncogene | volume = 20 | issue = 34 | pages = 4640–9 | date = August 2001 | pmid = 11498787 | doi = 10.1038/sj.onc.1204625 }}</ref> MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.<ref name="pmid22366898">{{cite journal | vauthors = Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP, Waisfisz Q, Rottenberg S, Boven E, Jonkers J, Jimenez CR | title = Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer | journal = Mol. Cell. Proteomics | volume = 11 | issue = 7 | pages = M111.013334 | date = July 2012 | pmid = 22366898 | pmc = 3394939 | doi = 10.1074/mcp.M111.013334 }}</ref> | |||
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> | |||
[[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> | |||
==HER2== | ==HER2== | ||
Revision as of 14:13, 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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Breast Cancer Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Breast cancer laboratory tests On the Web |
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American Roentgen Ray Society Images of Breast cancer laboratory tests |
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Risk calculators and risk factors for Breast cancer laboratory tests |
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]
- 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.
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]
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
- ↑ 1.0 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
- ↑ National Center for Biotechnology Information, U.S. National Library of Medicine EntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)
- ↑ "BRCA1 gene tree". Ensembl.
- ↑ 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.
- ↑ Kimball's Biologh Pages
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.