1. NF1. The discovery of genes for familial mendelian cancer syndromes has provided the hypothesis regarding normal control of cell growth. In type 1 neurofibromatosis, positional cloning efforts unveiled a previously unknown gene on chromosome 17q. When mutated this 17q chromosome produces a clinical picture of cafe au lait spots, neurofibromas, Lisch nodules of the iris, and a predisposition to neurofibrosarcoma and glioma. The responsible gene is neurofibromin (NF1).

2. ret. So far we know that most autosomal dominant inherited cancer syndromes are due to mutations in tumour suppressor genes. However, there are a few interesting exceptions. Multiple endocrine neoplasia type 2 is a dominant disorder characterized by pituitary adenomas, medullary carcinoma of the thyroid, and in some pedigrees , phaechromocytoma. This neoplasia is due to gain of function mutations in the oncogene ret on chromosome 10. Conversely, loss of function mutations in ret cause Hirchsprung's disease or aganglionic megacolon.

3. HNPCC mismatch repair genes.

Dominantly inherited colon cancer may be associated with familial polyposis. This is usually due to mutations in the adenomatous polyposis coli tumour suppressor gene on chrosome 5.

However, in most families with colon cancer , the affected members do not have familial polyposis. The cancer arises from normal epithelium, and is known as hereditary nonpolyposiscolon cancer, HNPCC or Lynch's syndrome. The criteria to diagnose HNPCC  require the occurence of colon cancer in at least three individuals over at least two generations with at least one individual diagnosed under the agew of 50. About 1 in 200 in the general population may have HNPCC. Most HNPCC is due to mutations in one of the four mismatched repair genes.

4. BRCA1 and BRCA2. These are dominantly inherited high penetrance susceptibility genes. They are not Mendelian cancer syndromes . I include it here for comparison and educational purposes.

In breast and ovarian cancer, a subset of 5 to 10% are due to these genes which were identified by positional cloning. BRCA1 on chromosome 17 when mutated produces a high risk of up to 85% lifelong of breast cancer and 50% lifelong risk for ovarian cancer. About 1 in 500 women carries a germline BRCA1 mutation often giving rise to strong family history.  Men with BRCA1 may have an increased risk of prostate cancer. BRCA2 on chromosome 13 mutations confers a high risk of breast cancer. Men with BRCA2 mutations are prone to develop breast cancer. The frequency of BRCA2 mutations is about half that of BRCA1.

How about the remaining 90 to 95 % of breast cancers without germline mutations in BRCA1 and BRCA2?