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
At least 20 families with germline mutation
in either KIT or PDGFRA have been described.