Genetic abnormalities in BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of HBOC cases can be ascribed to BRCA1 and BRCA2 mutations.
Next-generation sequencing approaches are uncovering novel HBOC factors among affected families without BRCA1 or BRCA2 mutations; at present more than 25 have emerged. New factors generally function in the same genome maintenance pathways as established HBOC factors, indicating substantial locus heterogeneity.
Disabled pathways in HBOC are homologous recombination repair (HRR), protection of stalling DNA replication forks, mismatch repair, and cell cycle checkpoint and DNA damage checkpoint control pathways.
The new pathogenic variants are rare, which poses challenges to the estimation of risk attribution through patient cohorts. There is a risk that patients or healthy carriers exhibiting pathogenic variants in rare HBOC genes may be excluded from the best possible treatment or presymptomatic screening programmes.
Structural and functional analysis can support variant classification in the context of international collaboration and standardized guidelines. Functional approaches are aided by extensive locus heterogeneity, which converges on a relatively small number of genome maintenance pathways that may be reconciled in vitro.
Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making.
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Broca, P. Traité des Tumeurs (ed. Asselin, P.) (Paris, 1866).
Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).This study describes the mapping of the BRCA1 gene.
Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).This study describes the mapping of the BRCA2 gene.
Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).
Chen, S. & Parmigiani, G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 25, 1329–1333 (2007).
Mavaddat, N. et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J. Natl Cancer Inst. 105, 812–822 (2013).
Tai, Y. C., Domchek, S., Parmigiani, G. & Chen, S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J. Natl Cancer Inst. 99, 1811–1814 (2007).
Campeau, P. M., Foulkes, W. D. & Tischkowitz, M. D. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum. Genet. 124, 31–42 (2008).
Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl Acad. Sci. USA 108, 18032–18037 (2011).
Kast, K. et al. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J. Med. Genet. 3, 465–471 (2016).
Cybulski, C. et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat. Genet. 47, 643–646 (2015).
Park, D. J. et al. Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer Discov. 4, 804–815 (2014).
Sun, J. et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genet. 11, e1005228 (2015).
Easton, D. F. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N. Engl. J. Med. 372, 2243–2257 (2015).This review summarizes the current knowledge of HBOC genes included in gene panels in relation to their estimated breast cancer risk.
Shiovitz, S. & Korde, L. A. Genetics of breast cancer: a topic in evolution. Ann. Oncol. 26, 1291–1299 (2015).
Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).
Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).This paper identifies a new role of BRCA2 in promoting DNA replication fork stability.
Prakash, R., Zhang, Y., Feng, W. & Jasin, M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7, a016600 (2015).
Lavin, M. F., Kozlov, S., Gatei, M. & Kijas, A. W. ATM-dependent phosphorylation of all three members of the MRN complex: from sensor to adaptor. Biomolecules 5, 2877–2902 (2015).
Paull, T. T. Mechanisms of ATM Activation. Annu. Rev. Biochem. 84, 711–738 (2015).
Stracker, T. H. & Petrini, J. H. The MRE11 complex: starting from the ends. Nat. Rev. Mol. Cell Biol. 12, 90–103 (2011).
Wang, H. et al. The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair. PLoS Genet. 9, e1003277 (2013).
Liu, J., Doty, T., Gibson, B. & Heyer, W. D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1260–1262 (2010).
Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).
Thorslund, T. et al. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1263–1265 (2010).
Jiang, Q. & Greenberg, R. A. Deciphering the BRCA1 tumor suppressor network. J. Biol. Chem. 290, 17724–17732 (2015).
Roy, R., Chun, J. & Powell, S. N. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat. Rev. Cancer 12, 68–78 (2012).
Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).
Bothmer, A. et al. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 207, 855–865 (2010).
Cao, L. et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35, 534–541 (2009).
Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–U656 (2010).
Bartkova, J. et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol. Oncol. 2, 296–316 (2008).
Bogdanova, N. et al. NBS1 variant I171V and breast cancer risk. Breast Cancer Res. Treat. 112, 75–79 (2008).
Damiola, F. et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case–control mutation-screening study. Breast Cancer Res. 16, R58 (2014).
Pennington, K. P. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20, 764–775 (2014).
Ramus, S. J. et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J. Natl Cancer Inst. 107, djv214 (2015).
Goldgar, D. E. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 13, R73 (2011).
Renwick, A. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38, 873–875 (2006).
Van Os, N. J. et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin. Genet. https://dx.doi.org/10.1111/cge.12710 (2015).
Grigaravicius, P. et al. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ. 23, 454–468 (2016).
Lin, X. et al. RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival. Mol. Cell. Biol. 27, 4905–4916 (2007).
Shakya, R. et al. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl Acad. Sci. USA 105, 7040–7045 (2008).
Lee, C. et al. Functional analysis of BARD1 missense variants in homology-directed repair of DNA double strand breaks. Hum. Mutat. 36, 1205–1214 (2015).
Westermark, U. K. et al. BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. Mol. Cell. Biol. 23, 7926–7936 (2003).
Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).
Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).
Buisson, R. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17, 1247–1254 (2010).
Ahlskog, J. K., Larsen, B. D., Achanta, K. & Sorensen, C. S. ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Rep. 17, 671–681 (2016).
Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422–426 (2015).
Suwaki, N., Klare, K. & Tarsounas, M. RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin. Cell Dev. Biol. 22, 898–905 (2011).
De Brakeleer, S. et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 31, E1175–E1185 (2010).
Erkko, H. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).
Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).
Golmard, L. et al. Germline mutation in the RAD51B gene confers predisposition to breast cancer. BMC Cancer 13, 484 (2013).
Song, H. et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J. Clin. Oncol. 33, 2901–2907 (2015).
Jonson, L. et al. Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer. Breast Cancer Res. Treat. 155, 215–222 (2016).
Loveday, C. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet. 43, 879–882 (2011).
Meindl, A. et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 42, 410–414 (2010).
Sopik, V., Akbari, M. R. & Narod, S. A. Genetic testing for RAD51C mutations: in the clinic and community. Clin. Genet. 88, 303–312 (2015).
Baker, J. L., Schwab, R. B., Wallace, A. M. & Madlensky, L. Breast cancer in a RAD51D mutation carrier: case report and review of the literature. Clin. Breast Cancer 15, e71–75 (2015).
Park, D. J. et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am. J. Hum. Genet. 90, 734–739 (2012).
Hilbers, F. S. et al. Rare variants in XRCC2 as breast cancer susceptibility alleles. J. Med. Genet. 49, 618–620 (2012).
Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38, 1239–1241 (2006).
Easton, D. F. et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 53, 298–309 (2016).
Rafnar, T. et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 43, 1104–1107 (2011).
Solyom, S. et al. Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Sci. Transl Med. 4, 122ra23 (2012).
Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012).
Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).
Chaudhuri, A. R. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016).
Murphy, A. K. et al. Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. J. Cell Biol. 206, 493–507 (2014).
Nikkila, J. et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat. Commun. 4, 2578 (2013).
Pathania, S. et al. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat. Commun. 5, 5496 (2014).
Sedic, M. et al. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat. Commun. 6, 7505 (2015).
Jeng, Y. M. et al. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 26, 6160–6166 (2007).
Croteau, D. L., Popuri, V., Opresko, P. L. & Bohr, V. A. Human RecQ helicases in DNA repair, recombination, and replication. Annu. Rev. Biochem. 83, 519–552 (2014).
Bogliolo, M. & Surralles, J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr. Opin. Genet. Dev. 33, 32–40 (2015).
Kiiski, J. I. et al. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc. Natl Acad. Sci. USA 111, 15172–15177 (2014).
Thompson, E. R. et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 8, e1002894 (2012).This is the first description of the use of exome sequencing data in the identification of putative novel HBOC genes.
Bogdanova, N. et al. Prevalence of the BLM nonsense mutation, Q548X, in ovarian cancer patients from Central and Eastern Europe. Fam. Cancer 14, 145–149 (2015).
Solyom, S. et al. Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family. Cancer Lett. 302, 113–118 (2011).
Ellingson, M. S. et al. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res. Treat. 153, 435–443 (2015).
Gardini, A., Baillat, D., Cesaroni, M. & Shiekhattar, R. Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation. EMBO J. 33, 890–905 (2014).
Gorski, J. J. et al. Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis. Nucleic Acids Res. 39, 9536–9548 (2011).
Bhatia, V. et al. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511, 362–365 (2014).Identifies a new role for BRCA2 in preventing transcription-induced stress at the replication fork.
Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).
Garcia-Rubio, M. L. et al. The Fanconi anemia pathway protects genome integrity from R-loops. PLoS Genet. 11, e1005674 (2015).
Pena-Diaz, J. & Jiricny, J. Mammalian mismatch repair: error-free or error-prone? Trends Biochem. Sci. 37, 206–214 (2012).
Vasen, H. F., Tomlinson, I. & Castells, A. Clinical management of hereditary colorectal cancer syndromes. Nat. Rev. Gastroenterol. Hepatol 12, 88–97 (2015).
Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305, 2304–2310 (2011).
Engel, C. et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J. Clin. Oncol. 30, 4409–4415 (2012).
Harkness, E. F. et al. Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J. Med. Genet. 52, 553–556 (2015).
ten Broeke, S. W. et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J. Clin. Oncol. 33, 319–325 (2015).
Alemayehu, A. & Fridrichova, I. The MRE11/RAD50/NBS1 complex destabilization in Lynch-syndrome patients. Eur. J. Hum. Genet. 15, 922–929 (2007).
de Wind, N., Dekker, M., Berns, A., Radman, M. & te Riele, H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330 (1995).
Tham, K. C., Kanaar, R. & Lebbink, J. H. Mismatch repair and homeologous recombination. DNA Repair (Amst.) 38, 75–83 (2016).
Shiloh, Y. ATM: expanding roles as a chief guardian of genome stability. Exp. Cell Res. 329, 154–161 (2014).
Smith, J., Tho, L. M., Xu, N. & Gillespie, D. A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 108, 73–112 (2010).
Zilfou, J. T. & Lowe, S. W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 1, a001883 (2009).
Fabbro, M. et al. BRCA1–BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J. Biol. Chem. 279, 31251–31258 (2004).
Shaltiel, I. A., Krenning, L., Bruinsma, W. & Medema, R. H. The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle. J. Cell Sci. 128, 607–620 (2015).
McBride, K. A. et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat. Rev. Clin. Oncol. 11, 260–271 (2014).
Gonzalez, K. D. et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J. Clin. Oncol. 27, 1250–1256 (2009).
Canman, C. E. et al. Activation of the ATM kinase by ionising radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).
Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).
Guo, Y., Feng, W., Sy, S. M. & Huen, M. S. ATM-dependent phosphorylation of the Fanconi anemia protein PALB2 promotes the DNA damage response. J. Biol. Chem. 290, 27545–27556 (2015).
Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).
Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31, 55–59 (2002).
Weischer, M. et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J. Clin. Oncol. 30, 4308–4316 (2012).
Huijts, P. E. et al. CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer. Eur. J. Hum. Genet. 22, 46–51 (2014).
Hartmann, L. C. & Lindor, N. M. The Role of risk-reducing surgery in hereditary breast and ovarian cancer. N. Engl. J. Med. 374, 454–468 (2016).
Sestak, I. & Cuzick, J. Update on breast cancer risk prediction and prevention. Curr. Opin. Obstet. Gynecol. 27, 92–97 (2015).
Cuzick, J. et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 361, 296–300 (2003).
King, M. C. et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286, 2251–2256 (2001).
Nichols, H. B., DeRoo, L. A., Scharf, D. R. & Sandler, D. P. Risk–benefit profiles of women using tamoxifen for chemoprevention. J. Natl Cancer Inst. 107, 354 (2015).
Cuzick, J. et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383, 1041–1048 (2014).
Tan, D. S. et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J. Clin. Oncol. 26, 5530–5536 (2008).
Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. https://dx.doi.org/10.1158/1078-0432.CCR-15-2477 (2016).
Gadducci, A. & Guerrieri, M. E. PARP inhibitors in epithelial ovarian cancer: state of art and perspectives of clinical research. Anticancer Res. 36, 2055–2064 (2016).
Rebbeck, T. R. et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313, 1347–1361 (2015).This study describes the risk of breast or ovarian cancer in relation to type and location of BRCA1 and BRCA2 mutations.
Jhuraney, A. et al. BRCA1 Circos: a visualisation resource for functional analysis of missense variants. J. Med. Genet. 52, 224–230 (2015).
Plon, S. E. et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat. 29, 1282–1291 (2008).This study describes the recommendations for a common classification system for variants in predisposing cancer genes.
Spurdle, A. B. et al. ENIGMA—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum. Mutat. 33, 2–7 (2012).
Complexo et al. COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration. Breast Cancer Res. 15, 402 (2013).
Eccles, D. M. et al. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann. Oncol. 26, 2057–2065 (2015).
Mooney, S. D. & Klein, T. E. The functional importance of disease-associated mutation. BMC Bioinformatics 3, 24 (2002).
Dixit, A., Torkamani, A., Schork, N. J. & Verkhivker, G. Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability. Biophys. J. 96, 858–874 (2009).
Gkeka, P. et al. Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant. PLoS Comput. Biol. 10, e1003895 (2014).
Lu, S., Jang, H., Nussinov, R. & Zhang, J. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci. Rep. 6, 21949 (2016).
Martin, A. C. et al. Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein. Hum. Mutat. 19, 149–164 (2002).
Lim, K. H., Ferraris, L., Filloux, M. E., Raphael, B. J. & Fairbrother, W. G. Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc. Natl Acad. Sci. USA 108, 11093–11098 (2011).
Sterne-Weiler, T., Howard, J., Mort, M., Cooper, D. N. & Sanford, J. R. Loss of exon identity is a common mechanism of human inherited disease. Genome Res. 21, 1563–1571 (2011).
Vallee, M. P. et al. Adding in silico assessment of potential splice aberration to the integrated evaluation of BRCA gene unclassified variants. Hum. Mutat. 37, 627–639 (2016).
Steffensen, A. Y. et al. Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur. J. Hum. Genet. 22, 1362–1368 (2014).
Colombo, M. et al. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum. Mol. Genet. 23, 3666–3680 (2014).
Fackenthal, J. D. et al. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. J. Med. Genet. https://dx.doi.org/10.1136/jmedgenet-2015-103570 (2016).
de la Hoya, M. et al. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum. Mol. Genet. https://dx.doi.org/10.1093/hmg/ddw094 (2016).
Guidugli, L. et al. Functional assays for analysis of variants of uncertain significance in BRCA2. Hum. Mutat. 35, 151–164 (2014).This paper reviews the methods used for functional analysis of BRCA2 variants.
Millot, G. A. et al. A guide for functional analysis of BRCA1 variants of uncertain significance. Hum. Mutat. 33, 1526–1537 (2012).This paper reviews the methods used for functional analysis of BRCA1 variants.
Starita, L. M. et al. Massively parallel functional analysis of BRCA1 RING domain variants. Genetics 200, 413–422 (2015).
Reid, L. J. et al. E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl Acad. Sci. USA 105, 20876–20881 (2008).
Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).
Guidugli, L. et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 73, 265–275 (2013).
Loke, J. et al. Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway. Hum. Mol. Genet. 24, 3030–3037 (2015).
Biswas, K. et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 118, 2430–2442 (2011).
Biswas, K. et al. Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. Hum. Mol. Genet. 21, 3993–4006 (2012).
Bouwman, P. et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 3, 1142–1155 (2013).
Chang, S., Biswas, K., Martin, B. K., Stauffer, S. & Sharan, S. K. Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. J. Clin. Invest. 119, 3160–3171 (2009).
Kuznetsov, S. G., Liu, P. & Sharan, S. K. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat. Med. 14, 875–881 (2008).This study describes the use of a stem cell-based assay to examine BRCA2 variants.
McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).
Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).
Woods, N. T. et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. Genom. Med. https://dx.doi.org/10.1038/npjgenmed.2016.1 (2016).
Drost, M. et al. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome. Proc. Natl Acad. Sci. USA 110, 9403–9408 (2013).
Hennessy, B. T., Coleman, R. L. & Markman, M. Ovarian cancer. Lancet 374, 1371–1382 (2009).
Narod, S. A. Breast cancer in young women. Nat. Rev. Clin. Oncol. 9, 460–470 (2012).
Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350, 1047–1059 (1997).
Lacey, J. V. Jr et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288, 334–341 (2002).
Rodriguez, C., Patel, A. V., Calle, E. E., Jacob, E. J. & Thun, M. J. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285, 1460–1465 (2001).
Kurman, R. J. & Shih, I. E. M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am. J. Pathol. 186, 733–747 (2016).
Narod, S. A. et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J. Natl Cancer Inst. 94, 1773–1779 (2002).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).
Guedj, M. et al. A refined molecular taxonomy of breast cancer. Oncogene 31, 1196–1206 (2012).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).
Prat, A. et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast 24 (Suppl. 2), S26–S35 (2015).
Van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).
Farmer, P. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005).
Prat, A. et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68 (2010).
Jonsson, G. et al. The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer. Cancer Res. 72, 4028–4036 (2012).
Larsen, M. J. et al. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling. PLoS ONE 8, e64268 (2013).
Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).This paper reviews the molecular features of BRCA-mutant tumours, the biomarkers used to identify BRCAness and BRCAness in relation to treatment with PARP inhibitors and platinum therapy.
Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).
Peng, G. et al. Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat. Commun. 5, 3361 (2014).
Timms, K. M. et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 16, 475 (2014).
Naipal, K. A. et al. Functional ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment. Clin. Cancer Res. 20, 4816–4826 (2014).
Morganella, S. et al. The topography of mutational processes in breast cancer genomes. Nat. Commun. 7, 11383 (2016).
Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).
Corso, G., Intra, M., Trentin, C., Veronesi, P. & Galimberti, V. CDH1 germline mutations and hereditary lobular breast cancer. Fam. Cancer 15, 215–219 (2016).
Guilford, P. J. et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum. Mutat. 14, 249–255 (1999).
Hansford, S. et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 1, 23–32 (2015).
Benusiglio, P. R. et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J. Med. Genet. 50, 486–489 (2013).
Petridis, C. et al. Germline CDH1 mutations in bilateral lobular carcinoma in situ. Br. J. Cancer 110, 1053–1057 (2014).
Ratner, N. & Miller, S. J. A. RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat. Rev. Cancer 15, 290–301 (2015).
Seminog, O. O. & Goldacre, M. J. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer 108, 193–198 (2013).
Sharif, S. et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J. Med. Genet. 44, 481–484 (2007).
Seminog, O. O. & Goldacre, M. J. Age-specific risk of breast cancer in women with neurofibromatosis type 1. Br. J. Cancer 112, 1546–1548 (2015).
Pulido, R. PTEN: a yin-yang master regulator protein in health and disease. Methods 77–78, 3–10 (2015).
Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67 (1997).
Leslie, N. R. & Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 52, 30–38 (2016).
Tan, M. H. et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 18, 400–407 (2012).
Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).
Fraser, M. et al. PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapy. Clin. Cancer Res. 18, 1015–1027 (2012).
Gupta, A. et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle 8, 2198–2210 (2009).
McEllin, B. et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 70, 5457–5464 (2010).
McCabe, N. et al. Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 75, 2159–2165 (2015).
Momcilovic, M. & Shackelford, D. B. Targeting LKB1 in cancer - exposing and exploiting vulnerabilities. Br. J. Cancer 113, 574–584 (2015).
Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).
Beggs, A. D. et al. Peutz–Jeghers syndrome: a systematic review and recommendations for management. Gut 59, 975–986 (2010).
Lim, W. et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126, 1788–1794 (2004).
Gupta, R., Liu, A. Y., Glazer, P. M. & Wajapeyee, N. LKB1 preserves genome integrity by stimulating BRCA1 expression. Nucleic Acids Res. 43, 259–271 (2015).
Sanger, F., Nicklen, S. & Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).
Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).
Watson, P. & Lynch, H. T. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71, 677–685 (1993).
Athma, P., Rappaport, R. & Swift, M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet. Cytogenet. 92, 130–134 (1996).
Schaner, M. E. et al. Gene expression patterns in ovarian carcinomas. Mol. Biol. Cell 14, 4376–4386 (2003).
Gorski, B. et al. Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int. J. Cancer 106, 379–381 (2003).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).These two studies describe the effects of PARP inhibition on BRCA-deficient cells.
Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).
Weischer, M., Bojesen, S. E., Ellervik, C., Tybjaerg-Hansen, A. & Nordestgaard, B. G. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J. Clin. Oncol. 26, 542–548 (2008).
Antoniou, A. C. et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 371, 497–506 (2014).
Cho, M. Y. et al. First report of ovarian dysgerminoma in Cowden syndrome with germline PTEN mutation and PTEN-related 10q loss of tumor heterozygosity. Am. J. Surg. Pathol. 32, 1258–1264 (2008).
Loveday, C. et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat. Genet. 44, 475–476; author reply 476 (2012).
Birch, J. M. et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20, 4621–4628 (2001).
The authors thank K. Cimprich for communicating results prior to publication and B. Ejlertsen for helpful comments on the manuscript. The authors thank the Danish Cancer Society (C.S.S.), the Danish Medical Research Council (C.S.S.), the Neye Foundation (F.C.N.) and the Research Foundation for Health Research of the Capital Region of Denmark (F.C.N. and T.v.O.H.) for funding of their work.
The authors declare no competing financial interests.
- Locus heterogeneity
A genetic term describing how variations in different genes cause the same disorder. The genes are not linked physically; examples are hereditary breast and ovarian cancer predisposition by BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and TP53.
- Homologous recombination repair
(HRR). A DNA repair pathway acting on DNA double-strand breaks that uses the undamaged sister chromatid as template for error-free repair. It is a multi-protein pathway involving a large number of factors, including BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and RAD51 genes.
- Mismatch repair
(MMR). A system for repairing erroneous insertion, deletion and misincorporation of bases arising during DNA replication. Mutations in MMR genes can result in microsatellite instability, which is implicated in most human cancers.
- Interstrand DNA crosslink repair
Interstrand crosslinks (ICLs) occur through the covalent joining of opposite strands of the DNA helix. ICLs occur after reaction of DNA with natural products of metabolism or with chemotherapeutic reagents such as platinum compounds. ICL repair requires several DNA repair pathways including Fanconi anaemia and homologous recombination repair (HRR).
- Fanconi anaemia
A bone marrow syndrome with enhanced predisposition to several cancers. It is a rare inherited disorder caused by mutations in several genes involved in the repair of DNA crosslinks, which includes the Fanconi anaemia factors FANCA and FANCE, BRCA1, BRCA2 and partner and localizer of BRCA2 (PALB2) genes.
- Genotoxic stress
Cellular exposure to environmental and endogenous agents or conditions that can lead to genome alterations. If unrepaired as cells resume the cell division cycle, the altered genetic information leads to mutations, which may lead to cancer.
- Cell cycle checkpoints
Signalling events during the cell cycle that prevent further progression.
- Cyclin-dependent kinase
(CDK). Member of a class of kinases that associate with partner proteins termed cyclins. Specific CDKs are active at various phases of the cell cycle to promote cell cycle progression.
- Platinum analogues
A class of chemotherapeutic agents, including cisplatin, oxaliplatin and carboplatin. Platinum compounds form intrastrand and interstrand crosslinks on DNA.
- poly-(ADP-ribose) polymerase
(PARP). A class of enzymes involved in facilitating DNA repair.
- Variant of unknown significance
(VUS). Variants in genes are classified according to their impact on the protein function. A variant with an unknown clinical function owing to lack of functional or clinical data is classified as a VUS.
Genetic examination of several family members to clarify whether a specific variant is linked to a disease or not.
- Mini-gene splicing analysis
A cell-based functional assay to establish whether a variant has an effect on splicing.
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Nielsen, F., van Overeem Hansen, T. & Sørensen, C. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 16, 599–612 (2016). https://doi.org/10.1038/nrc.2016.72
A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance
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