Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer
Westphalen, Alexander ; Russell, Anna ; Buser, Mauro ; Berthod, Claudine ; Hutter, Pierre ; Plasilova, Martina ; Mueller, Hansjakob ; Heinimann, Karl
In: Human Genetics, 2005, vol. 116, no. 6, p. 461-465
Ajouter à la liste personnelle- Summary
- Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62years. Descendants of HNPCC patients (median age at diagnosis 39years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47years, IQR=10), with the median of the paired age difference amounting to 8years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC families