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Hereditary breast cancer

Written2000-11Kaija Holli
Department of Palliative Medicine, Department of Oncology, Tampere University Hospital, Tampere, Finland

(Note : for Links provided by Atlas : click)


Other namesSite-specific breast cancer
Familiar breast-ovarian cancer
Atlas_Id 10062
Genes implicated inATM   BARD1   BRIP1   BRCA1   BRCA2   CASP8   CDH1   CHEK2   ESR1   HMMR   NQO2   PALB2   PHB   PPM1D   PTEN   RAD51   RAD54L   STK11   TP53   XRCC3  
Note hereditary or familiar form of breast cancerwith a familiar background
  • follows an autosomal dominant pattern
  • 5-10 % of all breast cancers have hereditary background
  • hereditary susceptibility for breast cancer has been counted to be 30-40 % of BRCA1 (see below, gene section), 10-30 % of BRCA2, less than 1 % of Tp 53, less than 1 % of PTEN and one third of unknown mutations; frequency of BRCA1 mutation is around 0.2 % in general population, 200 carriers among 100 000 individuals.
  • Clinics

    Note hereditary breast cancer is a heterogenous entity including several clinical variants
    Phenotype and clinics "site specific breast cancer" is characterized by the predominance of breast cancer, while "hereditary breast-ovarian cancer" has neoplasms in both organs
  • BRCA1 mutation carrier (chromosome 17q12-21) has early age at onset, and lifetime risk for breast cancer 50 % - 85 % and ovarian cancer 15 %-45 %; about 500 different mutations have been reported; possible increased risk of prostate cancer and colon cancer
  • BRCA2 (chromosome 13q12-13) mutation carrier has risk for breast cancer 30 %-85 %; about 300 different mutations have been reported; it is also associated for male breast cancer (6 %) and ovarian breast cancer (10% -20%); increased risk of prostate, laryngeal cancer and pancreatic cancer.
  • other genetic conditions associated with increased breast cancer risk are:
  • Li-Fraumeni syndroma (p53 mutation on chromosome 17p13) is characterized by very early onset of neoplasms, including soft tissue sarcoma, osteosarcoma, brain tumours, leukemia, lung cancer, laryngeal cancer and adrenocorteal cancer.; lifetime risk for cancer: about 90 % for women and 70 % for men
  • Cowden syndroma (PTEN, 10q23) is a rare type of autosomal dominant inherited condition of multiple hamartomas with increased risk of bilateral breast cancers and thyroid tumours
  • Muir-Torre Syndroma ( MSH2 , MLH1), with also cancers of the gastro intestinal (GI)-tract, skin, genito urinary (Gu)-system
  • Peutz-Jeghers Syndroma, with also abnormal melarin deposits, GI-polyposis, cancers of the GI-tract, uterus, ovary and testis.
  • Ataxia-teleangiectasia (linked to chromosome 11q21) autosomal recessive disorder with many clinical signs including increased risk for breast cancer; homozygous AT carriers have around 100-fold risk of cancer
  • one third of familiar breast cancers with hereditary background is still unknown; recent findings indicated that genotyping "BRCA3" locus at 13q and "BRCA2" locus at 2q may lead identifing the next mutations.
  • breast cancers of BRCA1 and, to lesser extent BRCA2 carriers differ from those of sporadic breast cancers: more high-grade tumours, pleomorphism, a higher mitotic count, less tubule formation, more often steroid receptor negative, DNA-aneuploid and more often higher s-phase fractions.
  • Treatment
  • prophylactic bilateral mastectomy (reduces the risk of about 90 %) and/or ovarian ablation. Chemoprevention (antiestrogens, aromataze inhibitors, retinoids) mainly in clinical trials (tamoxifen may reduce the risk about 45 %).
  • early detection of cancers by screening mammograms (ultrasound) yearly, palpation, transvaginal ultrasound.
  • Prognosis prognosis is more dependent on extent of the disease at diagnosis than on the hereditary susceptibility

    Genes involved and Proteins

    Note see also breast cancer
    Gene NameBRCA1 (breast cancer 1, early onset)
    Location 17q21.31
    Description 22 coding exons spanning over 70 kb of genomic DNA the BRCA1 mRNA has a size of 7.8 kb
    Description the corresponding protein has 1863 amino acids, and 190-220 kDa
    Expression wide
    Function involved in DNA replication, repair transcriptional activation, cell cycle progression
    Germinal more than 500 sequence variations of the germline level have been reported

    Gene NameBRCA2 (breast cancer 2, early onset)
    Location 13q13.1
    Description gene spanning more than 17 kb of genomic DNA; the coding sequence comprisons 26 exons (10 254 nucleotides)
    Description the corresponding protein has 3 418 amino acid residives (384 kDa)
    Germinal more than 300 unique germ-line mutations have been reported

    Gene NameTP53 (Tumour protein p53 (Li-Fraumeni syndrome))
    Location 17p13.1
    Description 11 exons
    Function gene p53 encodes an ubiquitous nuclear protein involved in the control of genome integrity by preventing cells dividing before DNA damage is repaired

    Gene NamePTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)
    Location 10q23.31
    Description 9 exons
    Description the PTEN protein (also called MMA1) is an evolutionary conserved dual-extensive similarity with the cyto-skeletal protein tensin
    Function tumour suppression since bi allealic inactivations, inactivating germline mutations are responsible for a cancer prone syndrome
    Germinal heterozygeous germline mutations are responsible for the Cowden disease

    Gene NameSTK11 (serine/threonine kinase 11)
    Location 19p13.3
    Description 10 exons spanning 23 kb
    Description 433 amino acids
    Expression wide
    Function serine/threonine kinase; tumor suppressor gene
    Homology heterozygous mutations are responsible for the Peutz-Jeghers syndrome

    Gene NameATM (ataxia telangiectasia mutated)
    Location 11q22.3
    Description 66 exons spanning 184 kb
    Description 3056 amino acids, 350 kDa
    Function at the cell cycle checkpoint; induces G1 phase arrest


    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 (9064) : 1505-1510.
    PMID 9167459
    Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.
    Easton DF, Ford D, Bishop DT
    American journal of human genetics. 1995 ; 56 (1) : 265-271.
    PMID 7825587
    Prophylactic mastectomy for genetic predisposition to breast cancer: the proband's story.
    Eeles R, Cole T, Taylor R, Lunt P, Baum M
    Clinical oncology (Royal College of Radiologists (Great Britain)). 1996 ; 8 (4) : 222-225.
    PMID 8870999
    Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?
    Eng C, Murday V, Seal S, Mohammed S, Hodgson SV, Chaudary MA, Fentiman IS, Ponder BA, Eeles RA
    Journal of medical genetics. 1994 ; 31 (6) : 458-461.
    PMID 8071972
    Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
    Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N
    Journal of the National Cancer Institute. 1998 ; 90 (18) : 1371-1388.
    PMID 9747868
    Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.
    Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST, Eng CM
    American journal of human genetics. 1998 ; 63 (1) : 45-51.
    PMID 9634504
    Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.
    Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M
    American journal of human genetics. 1998 ; 62 (3) : 676-689.
    PMID 9497246
    Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.
    Kainu T, Juo SH, Desper R, Schaffer AA, Gillanders E, Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, Bailey-Wilson J, Kallioniemi OP, Tirkkonen M, Syrjäkoski K, Kuukasjärvi T, Koivisto P, Karhu R, Holli K, Arason A, Johannesdottir G, Bergthorsson JT, Johannsdottir H, Egilsson V, Barkardottir RB, Johannsson O, Haraldsson K, Sandberg T, Holmberg E, Grönberg H, Olsson H, Borg A, Vehmanen P, Eerola H, Heikkila P, Pyrhönen S, Nevanlinna H
    Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (17) : 9603-9608.
    PMID 10944226
    Hereditary cancer: two hits revisited.
    Knudson AG
    Journal of cancer research and clinical oncology. 1996 ; 122 (3) : 135-140.
    PMID 8601560
    Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.
    Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D, Bignon YJ, Struewing JP, Spurr NK, Bishop DT, Klijn JG, Devilee P, Cornelisse CJ, Lasset C, Lenoir G, Barkardottir RB, Egilsson V, Hamann U, Chang-Claude J, Sobol H, Weber B, Stratton MR, Easton DF
    Journal of the National Cancer Institute. 1998 ; 90 (15) : 1138-1145.
    PMID 9701363
    Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.
    Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR
    Journal of the National Cancer Institute. 1999 ; 91 (11) : 943-949.
    PMID 10359546
    The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.
    Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA
    The New England journal of medicine. 1997 ; 336 (20) : 1401-1408.
    PMID 9145676
    Population-based study of risk of breast cancer in carriers of BRCA2 mutation.
    Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjörd JE
    Lancet. 1998 ; 352 (9137) : 1337-1339.
    PMID 9802270


    This paper should be referenced as such :
    Holli, K
    Hereditary breast cancer
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):66-68.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 12 ]

    PPP1R9B RAD51D

    REVIEW articlesautomatic search in PubMed
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    indexed on : Mon Sep 7 18:35:36 CEST 2020

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