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Genetics

  • Ian Fentiman
Chapter

Abstract

Genetic studies have demonstrated multiple differences between male and female breast cancer, most noticeably that mutations of BRCA1 play a very small role in MBC whereas those of BRCA2 may be associated with up to 14% of male cases. Mutations of PALB2, partner and localiser of BRCA2, have been found in 16% of MBC cases, with or without a family history. In a large genome wide association study a common variant of RAD51B, a low penetrance gene, was found to be significantly associated with MBC. The EMSY gene is amplified in 13% of sporadic FBC but in 35% of MBC, with low amplification in BRCA2 associated cancers. Mutations of androgen receptor gene and CYP17 are rare in MBC. Bacterial artificial chromosome (BAC) arrays have revealed more genomic gains and fewer genomic losses in MBC, identifying 2 subgroups: male-complex and male-simple, the latter being found only in men. Genetic testing should be considered in men having one first degree relative with MBC and ≥1 with FBC or ovarian cancer since among this group, mutations have been found in 36%.

Keywords

Bacterial Artificial Chromosome BRCA2 Mutation BRCA2 Mutation Carrier Copy Number Change Female Breast Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Marger D, Urdaneta M, Fischer JJ. Breast cancer in brothers. Case Reports and a review of 30 Cases of male breast cancer. Cancer. 1975;36:458–61.CrossRefPubMedGoogle Scholar
  2. 2.
    Hill A, Yagmur Y, Tran KN, Bolton JS, Robson M, Borgen PI. Localized male breast carcinoma and family history. An analysis of 142 patients. Cancer. 1999;86:821–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Rosenblatt KA, Thomas DB, McTiernan A, Austin MA, Stalsberg H, et al. Breast cancer in men: aspects of familial aggregation. J Natl Cancer Inst. 1991;83:849–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Storm HH, Olsen J. Risk of breast cancer in offspring of male breast-cancer patients. Lancet. 1999;353:209.CrossRefPubMedGoogle Scholar
  5. 5.
    Teixeira MR, Pandis N, Dietrich CU, Reed W, Andersen J, et al. Chromosome banding analysis of gynecomastias and breast carcinomas in men. Genes Chromosom Cancer. 1998;23:16–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Lacle MM, Kornegoor R, Moelans CB, Maes-Verschuur AH, van der Pol C, et al. Analysis of copy number changes on chromosome 16q in male breast cancer by multiplex ligation-dependent probe amplification. Mod Pathol. 2013;26:1461–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Jacobs PA, Maloney V, Cooke R, Crolla JA, Ashworth A, Swerdlow AJ. Male breast cancer, age and sex chromosome aneuploidy. Br J Cancer. 2013;108:959–63.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265:2088–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, et al. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet. 1994;7:103–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Thorlacius S, Tryggvadottir L, Olafsdottir GH, Jonasson JG, Ogmundsdottir HM, et al. Linkage to BRCA2 region in hereditary male breast cancer. Lancet. 1995;346:544–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996;13:117–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Basham VM, Lipscombe JM, Ward JM, Gayther SA, Ponder BA, et al. BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res. 2002;4(1):R2.CrossRefPubMedGoogle Scholar
  14. 14.
    Thompson D, Easton D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001;68:410–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Deb S, Jene N, Kconfab Investigators, Fox SB. Genotypic and phenotypic analysis of familial male breast cancer shows under representation of the HER2 and basal subtypes in BRCA-associated carcinomas. BMC Cancer. 2012;12:510. doi: 10.1186/1471-2407-12-510.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sverdlov RS, Barshack I, Bar Sade RB, Baruch RG, Hirsh-Yehezkel G, et al. Genetic analyses of male breast cancer in Israel. Genet Test. 2000;4:313–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39:165–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Adank MA, van Mil SE, Gille JJ, Waisfisz Q, Meijers-Heijboer H. PALB2 analysis in BRCA2-like families. Breast Cancer Res Treat. 2011;127:357–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Ding YC. Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat. 2011;126:771–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Blanco A, de la Hoya M, Balmaña J, Ramón y Cajal T, Teulé A, et al. Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer. Breast Cancer Res Treat. 2012;132:307–15.CrossRefPubMedGoogle Scholar
  21. 21.
    Fernandes PH, Saam J, Peterson J, Hughes E, Kaldate R, et al. Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer. Cancer. 2014;120:963–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Vietri MT, Caliendo G, Casamassimi A, Cioffi M, De Paola ML, et al. A novel PALB2 truncating mutation in an Italian family with male breast cancer. Oncol Rep. 2015;33:1243–7.PubMedGoogle Scholar
  23. 23.
    Silvestri V, Zelli V, Valentini V, Rizzolo P, Navazio AS, et al. Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. Cancer. 2016; doi: 10.1002/cncr.30337. [Epub ahead of print].PubMedGoogle Scholar
  24. 24.
    Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42:406–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42:410–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Orr N, Lemnrau A, Cooke R, Fletcher O, Tomczyk K, et al. Genome-wide association study identifies a novel variant in RAD51B associated with male breast cancer risk. Nat Genet. 2012;44:1182–4.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hughes-Davies L, Huntsman D, Ruas M, Fuks F, et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell. 2003;115:523–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Navazio AS, Rizzolo P, Silvestri V, Valentini V, Zelli V, et al. EMSY copy number variation in male breast cancers characterized for BRCA1 and BRCA2 mutations. Breast Cancer Res Treat. 2016;160:181–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Lose F, Arnold J, Young DB, Brown CJ, Mann GJ, et al. BCoR-L1 variation and breast cancer. Breast Cancer Res. 2007;9(4):R54.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Deb S, Do H, Byrne D, Jene N, kConFab Investigators, et al. PIK3CA mutations are frequently observed in BRCAX but not BRCA2 -associated male breast cancer. Breast Cancer Res. 2013;15:R69. http://breast-cancer-research.com/content/15/4/CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Deb S, Wong SQ, Li J, Do H, Weiss J, et al. Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations. Br J Cancer. 2014;111:2351–60.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wooster R, Mangion J, Eeles R, Smith S, Dowsett M, et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet. 1992;2:132–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Lobaccaro J-M, Lumbroso S, Belon C, Galtler-Dereure F, et al. Androgen receptor gene mutation in male breast cancer. Hum Mol Genet. 1993;2:1799–802.CrossRefPubMedGoogle Scholar
  34. 34.
    Haraldsson K, Loman N, Zhang Q-X, Johannsson O, Olsson H, Borg A. BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease. Cancer Res. 1998;58:1367–71.PubMedGoogle Scholar
  35. 35.
    Young IE, Kurian KM, MAF M, Kunkler IH, Cohen BB, et al. The CAG repeat within the androgen receptor gene in male breast cancer patients. J Med Genet. 2000;37:139–40.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Syrjäkoski K, Hyytinen ER, Kuukasjärvi T, Auvinen A, Kallioniemi OP, et al. Androgen receptor gene alterations in Finnish male breast cancer. Breast Cancer Res Treat. 2003;77:167–70.CrossRefPubMedGoogle Scholar
  37. 37.
    Carey AH, Waterworth D, Patel K, White D, Little J, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994;3:1873–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Young IE, Kurian KM, MacKenzie MAF, Kunkler IH, Cohen BB, et al. A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer. Br J Cancer. 2000;82:1247–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Young IE, Kurian KM, Annink C, Kunkler IH, Anderson VA, et al. A polymorphism in the CYP17 gene is associated with male breast cancer. Br J Cancer. 1999;81:141–3.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gudmundsdottir K, Thorlacius S, Jonasson JG, Sigfusson BF, Tryggvadottir L, Eyfjord JE. CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status. Br J Cancer. 2003;88:933–6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. The CHEK2–Breast Cancer Consortium. Nat Genet. 2002;31:55–9.Google Scholar
  42. 42.
    Offit K, Pierce H, Kirchhoff T, Kolachana P, Rapaport B, et al. Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet. 2003;4:1.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Neuhausen S, Dunning S, Steele L, Yakumo K, Hoffman M. Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer. 108:477–8.Google Scholar
  44. 44.
    Ohayon T, Gal I, Baruch RG, Szabo C, Friedman E. CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer. 2004;108:479–80.CrossRefPubMedGoogle Scholar
  45. 45.
    Easton DF, Pooley KA, Dunning AM, PDP P, Thompson D, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447:1087–93.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Orr N, Cooke R, Jones M, Fletcher O, Dudbridge F, et al. Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men. PLoS Genet. 2011;7(9):e1002290. doi: 10.1371/journal.pgen.1002290.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Johansson I, Lauss M, Holm K, Staaf J, Nilsson C, et al. Genome methylation patterns in male breast cancer – Identification of an epitype with hypermethylation of polycomb target genes. Mol Oncol. 2015;9:1565–79.CrossRefPubMedGoogle Scholar
  48. 48.
    Piscuoglio S, Ng CK, Murray MP, Guerini-Rocco E, Martelotto LG. The genomic landscape of male breast cancers. Clin Cancer Res. 2016. pii: clincanres.2840.2015. [Epub ahead of print].Google Scholar
  49. 49.
    Lerman C, Schwartz MD, Lin TH, Hughes C, Narod S, Lynch HT. The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol. 1997;65:414–20.CrossRefPubMedGoogle Scholar
  50. 50.
    Zanna I, Rizzolo P, Sera F, Falchetti M, Aretini P, et al. The BRCAPRO 5.0 model is a useful tool in genetic counseling and clinical management of male breast cancer cases. Eur J Hum Genet. 2010;18:856–8.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kast K, Rhiem K, Wappenschmidt B, Hahnen E, Hauke J, et al. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J Med Genet. 2016;53:465–71.CrossRefPubMedGoogle Scholar
  52. 52.
    Deb S, Lakhani SR, Ottini L, Fox SB. The cancer genetics and pathology of male breast cancer. Histopathology. 2016;68:110–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Silvestri V, Barrowdale D, Mulligan AM, Neuhausen SL, Fox S, et al. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res. 2016;18(1):15. doi: 10.1186/s13058-016-0671-y.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Ian Fentiman
    • 1
  1. 1.Research OncologyGuy’s HospitalLondonUnited Kingdom

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