Hereditary Nonpolyposis Colorectal Cancer in 95 Families: Differences and Similarities between Mutation-Positive and Mutation-Negative Kindreds

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) describes the condition of a disparate group of families that have in common a predisposition to colorectal cancer in the absence of a premalignant phenotype. The genetic basis of this disease has been linked to mutations in genes associated with DNA mismatch repair. A large proportion of families harbor changes in one of two genes, hMSH2 and hMLH1. Approximately 35% of families in which the diagnosis is based on the Amsterdam criteria do not appear to harbor mutations in DNA-mismatch-repair genes. In this report we present data from a large series of families with HNPCC and indicate that there are subtle differences between families that harbor germline changes in hMSH2 and families that harbor hMLH1 mutations. Furthermore, there are differences between the mutation-positive group (hMSH2 and hMLH1 combined) of families and the mutation-negative group of families. The major findings identified in this study focus primarily on the extracolonic disease profile observed between the mutation-positive families and the mutation-negative families. Breast cancer was not significantly overrepresented in the hMSH2 mutation-positive group but was overrepresented in the hMLH1 mutation-positive group and in the mutation-negative group. Prostate cancer was not overrepresented in the mutation-positive groups but was overrepresented in the mutation-negative group. In age at diagnosis of colorectal cancer, there was no difference between the hMSH2 mutation-positive group and the hMLH1 mutation-positive group, but there was a significant difference between these two groups and the mutation-negative group.

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

“…(2001) and from Talseth‐Palmer et al. (2010) which presented data from 32 ( MLH1 or MSH2 ) and 35 ( MSH6 or PMS2 ) mutation positive families, respectively.…”

Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

“…There are conflicting reports on a possible increased risk of breast cancer in families with HNPCC/Lynch syndrome [6,[9][10][11][12][13][14]. Though breast cancer is not considered part of the tumor spectrum, MMR defective breast cancer has been described in a number of mutation carriers [10,11,[15][16][17][18][19].…”

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

“…It has been estimated that only 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene (Caldas et al, 1999). Stomach cancer has also been shown to be part of the tumour spectrum in other inherited syndromes, including hereditary non-polyposis colon cancer, otherwise known as HNPCC (Scott et al, 2001a), familial adenomatous polyposis (FAP) (Scott et al, 2001b), Peutz -Jeghers syndrome (Hizawa et al, 1993), Cowden's syndrome (Hamby et al, 1995) and the Li -Fraumeni syndrome (Scott et al, 1993).…”