Breast Cancer Susceptibility
Breast Cancer Susceptibility
Inherited breast cancer represents approximately 7% of all breast cancer.1 Highly penetrant mutations in the two main causal genes, BRCA1 and BRCA2, explain anywhere between 20% to 80% of strongly familial breast cancer cases, with a progressively decreasing contribution in pedigrees with fewer affected family members.2,3 Loci with low-to-intermediate rather than high penetrance following a polygenic mode of inheritance are thought to underlie a substantial portion of the remaining cases of inherited breast cancer.4-8 This theory has been supported empirically as most breast cancer associated genes identified since the discovery of BRCA1 and BRCA2 appear to confer low to moderate elevation in breast cancer risk.7
Our breast cancer test includes seven moderate-to-highly penetrant genes: TP53, whose defects increase the risk of breast cancer at least 10 fold over that of the general population, as well as six additional genes whose germline mutations typically confer risk of 2-10 fold: ATM, CDH1, CHEK2, PALB2, PTEN, and STK11. Estimates of penetrance (8% to 90%) and combined prevalence (5% to 10%) of mutations in these genes in inherited breast cancer are approximate and vary widely, as they are conditional on the study population, mutation, cancer subtype, and syndromic association.8-11
Tumor protein p53 (TP53) is a multifunctional tumor suppressor involved in transcriptional regulation, DNA repair, cell cycle arrest, and apoptosis.12 Germline mutations in TP53 gene represent the most frequent cause of Li-Fraumeni syndrome (LFS)12 and account for 2%-7% of early-onset breast cancer (i.e., onset before 30 years of age).13-15 Breast cancer is the most frequent type of cancer in female mutation carriers, with a median onset age of 33.16,17 The likelihood of finding TP53 mutations increases from 4%-7% in women with isolated, early-onset breast cancer to between 22% and 38% in women with a personal history of bilateral breast cancer or other LFS tumors, or with a family history of breast cancer or LFS.18-20 According to a recent review, by age 60, breast cancer penetrance of germline mutations in TP53 is approximately 90%.21 The most frequently identified mutations in the context of breast cancer are missense mutations disturbing normal binding and activation of TP53 target genes.22-24
Cadherin 1 (CDH1) is another tumor suppressor and a member of a family of transmembrane glycoproteins participating in cell-cell adhesion, differentiation, cell motility, and signaling.25 Mutations that abolish cellular adhesion are believed to facilitate metastasis.26 In addition to the risk of gastric cancer of 83%, women with CDH1 germline mutations also have an elevated risk of 39% to 60% for, in particular, lobular breast cancer with a mean onset age of 53.27-29 As is the case with PTEN and STK11, germline mutations in CDH1 are thought to represent rare causes of inherited breast cancer.9
Phosphatase and tensin homolog protein gene (PTEN) also encodes a tumor suppressor which initiates cell cycle arrest or apoptosis, depending on its cellular location.30-32 Germline mutations in PTEN are a major cause of Cowden syndrome - a multiple hamartoma syndrome with elevated cancer risk and a prevalence of one in 200,000.30 Breast cancer is its most common malignancy.30 Female mutation carriers have a lifetime risk of breast cancer of 25%-50%, with an average age of diagnosis between 38 and 46 years.21,33 In contrast to TP53-associated breast cancer, PTEN germline mutations have been reported in both females and males with breast cancer.34
Serine/threonine protein kinase 11 (STK11) is involved in the suppression of cellular proliferation and apoptosis.35 Mutations in STK11 explain 100% of familial and about 90% of nonfamilial cases of Peutz-Jeghers syndrome (PJS), which predisposes to gastrointestinal polyposis, mucocutaneous pigmentation and cancer.35 STK11 mutations also confer a risk of female breast cancer of 8% by age 40 and of 30% by age 65.36,37 Truncating mutations appear to be enriched in patients with PJS that ultimately develop breast cancer.38
Heterozygous, germline mutations in ATM (Ataxia-telangiectasia-mutated gene) may be responsible for up to 2% of familial breast cancer.10 The risk conferred is conditional on the type of mutation and may range from 2 to more than 10 fold.9,10,39 Some evidence to date suggests missense mutations40 as largely responsible for breast cancer predisposition, although they are less common in patients affected with ataxia telangiectasia, a disorder characterized by biallelic rather than monoallelic ATM mutations.41 Functional assays indicate that selected missense ATM mutations exert a dominant negative effect,42 interfering with normal ATM functions such as detection of double-stranded DNA breaks, regulation of cell-cycle checkpoints, and coordination of DNA repair.43
Monoallelic PALB2 (Partner and localizer of BRCA2 gene) mutations are found in 0.6% to 2.9% of familial breast cancer cases.9,11,44,45 An average breast cancer risk associated with a PALB2 germline mutation is estimated to be around 2.3 fold in families negative for BRCA1/2 defects.4 As is the case with ATM, however, the risk may vary depending on the specific alteration: Presence of a highly penetrant mutation (c.3113G>A) in an Australian population, for example, carried a lifetime risk of 90% by age 70,46 while the 1592delT mutation studied in a Finish sample conferred a risk increase of 4-fold.47 A large majority of the PALB2 mutations associated with breast cancer susceptibility are truncating and include small insertions, deletions, and nonsense mutations.40,44 Truncating mutations that abrogate the WD40-repeats functional domain are thought to disrupt the BRCA1–PALB2–BRCA2 complex and, consequently, the normal repair of double-stranded breaks.11,48 Other phenotypes caused by PALB2 are Fanconi anemia N and prostate cancer. FANCN/PALB2-associated tumours are typically ER and HER2 negative.11
Like the majority of proteins encoded by susceptibility genes for inherited breast cancer, the Cell-cycle–checkpoint kinase 2 (CHEK2) is involved in the repair of damaged DNA. CHEK2 germline mutations may account for 3% to 5% of cases of inherited breast cancer,6,9 and increase the risk between 2 and 5 fold, with the attendant lifetime risk of 37%-59%, depending on the presence of family history and bilateral disease.49,50 While some of these mutations have lower penetrance, the expressivity can be severe.49,51 A frequently reported CHEK2 mutation is the 1100delC mutation, associated with a lifetime risk of breast cancer of 15-20%,52 with differences in risk based on sex (risk of 2-3 fold in women and 10 fold in men) and age of onset (higher penetrance in early-onset breast cancer).53-55
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