Hereditary predisposition to cancer

HT Lynch MD^a, J Lynch BSN^a, S Coronel MPH^a, T Attard MD^b, P Watson PhD^a

^aDepartment of Preventive Medicine and Public Health, School of Medicine, Creighton University, California Plaza, Nebraska, Omaha, ^bDepartment of Pediatric Gastroenterology, University of Nebraska, 985160 Nebraska Medical Center, Omaha, Nebraska, United States

Aim: To discuss Creighton’s Hereditary Cancer resource with attention to its magnitude, mutation test results, medical records, pathology specimens and frozen specimens with attention to their research utilization in selected cancer prone pedigrees. Methods: Particular attention is given to a comprehensive family cancer history with meticulous coverage of genealogy, pathology verification, age of cancer onset, pattern of multiple primary cancers, their distribution within and between families, gene linkage and more recently, molecular genetic studies which have been under investigation at Creighton for more than 35 years. This has involved multiple collaborations nationally and internationally, given Creighton’s referral base and the wide geographic dispersion of cancer prone families. We have studied 2,071 families comprised of more than 162,000 individuals of whom 32,000 are alive and at-risk. A subset of families have participated in studies aimed at identifying cancer causing germline mutations. Mutations have been found in 208 families and in 2,939 members of these families. Nineteen thousand tumor records, 1,054 tumor pathology specimens and 5,507 frozen specimens are available in the resource. Conclusions: This work has contributed to the identification of an increasing number of hereditary cancer syndromes inclusive of families with multiple myeloma, the hereditary breast ovarian cancer syndrome characterized by BRCA1/BRCA2 germline mutations, the Lynch syndrome of which mismatch repair mutations, the most common of which are MSH2 and MLH1 have been identified, and the familial atypical multiple mole melanoma (FAMMM) syndrome, more recently linked to pancreatic carcinoma and sarcomas, of which the CDKN2A (p16) mutation has been identified. We will also discuss hereditary diffuse gastric cancer, and the E-cadherin mutation with implications for prophylactic gastrectomy in mutation carriers. The power of family studies will be described through the depiction of several “challenging pedigrees” which characterize these syndromes, and which illustrate the many research opportunities and their translation for surveillance and management, in the interest of improved cancer control for high risk family members.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in keynote session 702 (Keynote).