Management of multiple endocrine neoplasia syndrome type 2 families in association with rare
germline mutations of the RET proto-oncogene.
Hereditary breast and ovarian cancer is characterized by a predisposition to premenopausal breast cancer in females, with the triple-negative (estrogen receptor/progesterone receptor negative [ER-/PR-] and human epidermal growth factor receptor 2 negative [HER2/neu-]) phenotype more commonly associated with
germline mutations in BRCA1 than BRCA2, although both can be seen (2); ovarian cancer; male breast cancer (3); prostate cancer (4); pancreatic cancer (5); and risks of other less commonly associated cancers.
Women who do not have a strong family history suggesting the possibility that they carry a
germline mutation or who do not have a documented
germline mutation were considered by the committee to be at average risk of ovarian and breast cancer.
All but one (a BRCA1 mutation) were
germline mutations.
Loss of expression of MLH1 may be due to
germline mutation in Lynch syndrome, or somatic hypermethylation of the MLH1 promoter region in sporadic MSI colorectal carcinoma.
The GAII correctly identified 2 of the 3
germline mutations but, as mentioned above, failed to identify 1
germline mutation in MSH2 owing to poor read coverage.
A familial form of hepatic adenomatosis involves
germline mutations of HNF1A and is associated with maturity-onset diabetes mellitus of youth, type 3 (MODY3).
Tumors arise in patients with LS because biallelic inactivating mutations (a
germline mutation and a somatic mutation) of these DNA MMR genes lead to defective DNA MMR, which then promotes tumorigenesis through mutations of oncogenes and tumor suppressor genes.
It is now recognized that at least 30% of these tumors are hereditary, caused by
germline mutations of at least 10 genes.
Patients with a microsatellite instability-high (MSI-H) phenotype that indicates MMR deficiency in their cancer may have a
germline mutation in 1 of several DNA MMR genes (eg, MLH1, MSH2, MSH6, or PMS2) or an altered EPCAM (TACSTD1) gene.
Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA
germline mutation status.
At least 20 families with
germline mutation in either KIT or PDGFRA have been described.
