Other Rare Breast and Ovarian Cancer-Associated Syndromes
Hereditary non-polyposis colorectal cancer (HNPCC)
HNPCC is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer. The condition is due to germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations. The MLH1 and MSH2 genes are the most common susceptibility genes for HNPCC, accounting for 80% to 90% of observed mutations,[253,254] followed by MSH6 and PMS2.[255,256,257,258,259,260] (Refer to the Lynch syndrome (LS) section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)
The lifetime risk for ovarian carcinoma in females with HNPCC is estimated to be up to 12%, and the reported relative risk of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected HNPCC.[261,262,263,264,265,266] Characteristics of HNPCC-associated ovarian cancers may include over-representation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), under-representation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.[267,268]
Prior studies suggest breast cancer risk in individuals with HNPCC is not elevated.[269,270] However, in approximately 50% of individuals with HNPCC who develop breast cancer, there is loss of MMR protein expression, which corresponds with the MMR gene mutation segregating in the family.
Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented. This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[272,273] Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset. Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.