Of all breast cancer cases, 5-10% can be attributed to germline mutations, and the high-susceptibility genes BRCA1 and BRCA2 account for about 25-28% of these cases. For the remainder, several genes of moderate and low penetrance have been discovered. Histopathologic characteristics have been studied in small cohorts, but for most of the known non-BRCA1/2-associated hereditary breast cancers, the histologic and immunohistochemical phenotypes are not yet identified. Particularly BRCA1 tumors are associated with a distinct morphology and immunohistochemical characteristics that differ from sporadic breast cancer of age-matched controls. The recognition of features characteristic of these mutations can be helpful to identify patients likely to carry a germline mutation and to assess which gene should be screened for first, in families with a high occurrence of breast and ovarian cancer.

Keywords:
Intrinsic subtypes, Hereditary breast cancer, BRCA mutation, Genotype/phenotype correlations
1.
Larsen MJ, Thomassen M, Gerdes AM, Kruse TA: Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer (Auckl) 2014;8:145-155.
2.
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-1689.
3.
Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, Friedman LS, et al.: Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet 1994;7:103-107.
4.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al.: Molecular portraits of human breast tumours. Nature 2000;406:747-752.
5.
Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
6.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al.: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003;100:8418-8423.
7.
Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al.: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005;11:5678-5685.
8.
Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al.: Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008;68:3108-3114.
9.
Rakha EA, Reis-Filho JS, Ellis IO: Basal-like breast cancer: a critical review. J Clin Oncol 2008;26:2568-2581.
10.
Alizadeh AA, Ross DT, Perou CM, van de Rijn M: Towards a novel classification of human malignancies based on gene expression patterns. J Pathol 2001;195:41-52.
11.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ: Strategies for subtypes - dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011;22:1736-1747.
12.
Malhotra GK, Zhao X, Band H, Band V: Histological, molecular and functional subtypes of breast cancers. Cancer Biol Ther 2010;10:955-960.
13.
Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P, et al.: How basal are triple-negative breast cancers? Int J Cancer 2008;123:236-240.
14.
Weigelt B, Baehner FL, Reis-Filho JS: The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. J Pathol 2010;220:263-280.
15.
Foulkes WD, Smith IE, Reis-Filho JS: Triple-negative breast cancer. N Engl J Med 2010;363:1938-1948.
16.
Gerdes AM, Cruger DG, Thomassen M, Kruse TA: Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families. Clin Genet 2006;69:171-178.
17.
Melchor L, Benitez J: The complex genetic landscape of familial breast cancer. Hum Genet 2013;132:845-863.
18.
Gracia-Aznarez FJ, Fernandez V, Pita G, Peterlongo P, Dominguez O, de la Hoya M, et al.: Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles. PloS One 2013;8:e55681.
19.
Huen MS, Sy SM, Chen J: BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol 2010;11:138-148.
20.
Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329-1333.
21.
Thompson D, Easton DF: Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94:1358-1365.
22.
Honrado E, Benitez J, Palacios J: Histopathology of BRCA1- and BRCA2-associated breast cancer. Crit Rev Oncol Hematol 2006;59:27-39.
23.
Gevensleben H, Bossung V, Meindl A, Wappenschmidt B, de Gregorio N, Osorio A, et al.: Pathological features of breast and ovarian cancers in RAD51C germline mutation carriers. Virchows Arch 2014;465:365-369.
24.
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 1997;349:1505-1510.
25.
Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V: Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer 1977;40:1365-1385.
26.
Eisinger F, Jacquemier J, Charpin C, Stoppa-Lyonnet D, Bressac-de Paillerets B, Peyrat JP, et al.: Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 1998;58:1588-1592.
27.
Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012;21:134-147.
28.
Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, et al.: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 2005;11:5175-5180.
29.
van der Groep P, van der Wall E, van Diest PJ: Pathology of hereditary breast cancer. Cell Oncol (Dordr) 2011;34:71-88.
30.
Crook T, Brooks LA, Crossland S, Osin P, Barker KT, Waller J, et al.: p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene 1998;17:1681-1689.
31.
Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD: TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res 2001;61:4092-4097.
32.
Apostolou P, Fostira F: Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int 2013;2013:747318.
33.
van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 2005;42:711-719.
34.
Armes JE, Egan AJ, Southey MC, Dite GS, McCredie MR, Giles GG, et al.: The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 1998;83:2335-2345.
35.
Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al.: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998;90:1138-1145.
36.
Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Gruvberger-Saal SK, Saal LH, et al.: The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer. Cancer Res 2012;72:4028-4036.
37.
Larsen MJ, Kruse TA, Tan Q, Laenkholm AV, Bak M, Lykkesfeldt AE, et al.: Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling. PloS One 2013;8:e64268.
38.
Vargas AC, Reis-Filho JS, Lakhani SR: Phenotype-genotype correlation in familial breast cancer. J Mammary Gland Biol Neoplasia 2011;16:27-40.
39.
Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010;42:410-414.
40.
Tedaldi G, Danesi R, Zampiga V, Tebaldi M, Bedei L, Zoli W, et al.: First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer. BMC Cancer 2014;14:478.
41.
Antoni L, Sodha N, Collins I, Garrett MD: CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat Rev Cancer 2007;7:925-936.
42.
Domagala P, Wokolorczyk D, Cybulski C, Huzarski T, Lubinski J, Domagala W: Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer. Breast Cancer Res Treat 2012;132:937-945.
43.
Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, et al.: Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 2003;72:270-280.
44.
Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski M, Debniak T, et al.: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004;75:1131-1135.
45.
Hollestelle A, Wasielewski M, Martens JW, Schutte M: Discovering moderate-risk breast cancer susceptibility genes. Curr Opin Genet Dev 2010;20:268-276.
46.
Nagel JH, Peeters JK, Smid M, Sieuwerts AM, Wasielewski M, de Weerd V, et al.: Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. Breast Cancer Res Treat 2012;132:439-448.
47.
Huzarski T, Cybulski C, Domagala W, Gronwald J, Byrski T, Szwiec M, et al.: Pathology of breast cancer in women with constitutional CHEK2 mutations. Breast Cancer Res Treat 2005;90:187-189.
48.
Cybulski C, Gorski B, Huzarski T, Byrski T, Gronwald J, Debniak T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 2006;12:4832-4835.
49.
Farshid G, Balleine RL, Cummings M, Waring P: Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing. Am J Surg Pathol 2006;30:1357-1366.
50.
Peto J: Breast cancer susceptibility - a new look at an old model. Cancer Cell 2002;1:411-412.
51.
Antoniou AC, Easton DF: Models of genetic susceptibility to breast cancer. Oncogene 2006;25:5898-5905.
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2015
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