Hereditary breast cancer

2000-11-01   Kaija Holli 

Department of Palliative Medicine, Department of Oncology, Tampere University Hospital, Tampere, Finland

Identity

Name

Hereditary breast cancer

Alias

Site-specific breast cancer , Familiar breast-ovarian cancer

Note

hereditary or familiar form of breast cancerwith a familiar background

Inheritance

  • 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.
  • Omim

    114480

    Mesh

    D001943

    Orphanet

    227535 Hereditary breast cancer

    Umls

    -

    Clinics

    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

    Description

    22 coding exons spanning over 70 kb of genomic DNA the BRCA1 mRNA has a size of 7.8 kb

    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

    Description

    gene spanning more than 17 kb of genomic DNA; the coding sequence comprisons 26 exons (10 254 nucleotides)

    Germinal

    more than 300 unique germ-line mutations have been reported

    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

    Description

    9 exons

    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

    Description

    10 exons spanning 23 kb

    Expression

    wide

    Function

    serine\/threonine kinase; tumor suppressor gene

    Homology

    heterozygous mutations are responsible for the Peutz-Jeghers syndrome

    Description

    66 exons spanning 184 kb

    Function

    at the cell cycle checkpoint; induces G1 phase arrest

    Bibliography

    Pubmed IDLast YearTitleAuthors
    91674591997Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.
    78255871995Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.Easton DF et al
    88709991996Prophylactic mastectomy for genetic predisposition to breast cancer: the proband's story.Eeles R et al
    80719721994Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?Eng C et al
    97478681998Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.Fisher B et al
    96345041998Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.Fodor FH et al
    94972461998Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.Ford D et al
    109442262000Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.Kainu T et al
    86015601996Hereditary cancer: two hits revisited.Knudson AG et al
    97013631998Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.Lakhani SR et al
    103595461999Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.Peto J et al
    91456761997The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.Struewing JP et al
    98022701998Population-based study of risk of breast cancer in carriers of BRCA2 mutation.Thorlacius S et al

    External Links