The population frequencies of the CDKN2A common variants remain undetermined. In Poland, there is a common variant of the CDKN2A: an alanine to threonine substitution (A148T), which has been detected in other populations. We have recently showed that it is significantly overrepresented among Polish melanoma patients when compared to general population. Herein, we ascertained the prevalence of the A148T variant in 3,583 unselected cancer cases and 3,000 random control subjects from the same Polish population. We evaluated eleven different malignancies, representing the majority of all common cancer sites. Positive association with A148T variant was observed for lung cancer (OR, 2.0; p 5 0.0052). A similar trend, although nonsignificant after the Bonferroni correction, was observed for colorectal cancer (OR, 1.5; p 5 0.5499). These results suggest that A148T variant may be associated with a multi-organ cancer risk in the Polish population. ' 2006 Wiley-Liss, Inc.Key words: CDKN2A; A148T variant; cancer risk The CDKN2A (OMIM 60160) is a tumor-suppressor gene that is regarded as a major malignant melanoma (MM) susceptibility gene. 1 The p16 protein is thought to be a cyclin-dependent kinase inhibitor that suppresses cell proliferation. 2 Thus far CDKN2A has been strongly implicated in predispositions to MM and pancreatic carcinoma. 3 Data from the literature indicate CDKN2A as a common MM/breast cancer susceptibility gene. 4 There is also some evidence to indicate a possible association between CDKN2A and head and neck cancer, 5 respiratory malignancies 6 and laryngeal cancer. 7 The p16 protein is expressed in a wide range of tissues, and the full range of cancers associated with CDKN2A mutations has yet to be determined.In Poland, there is one common variant of CDKN2A-an alanine to threonine substitution at codon 148 (A148T)-which has been estimated to be present in approximately 3-3.5% of the population. 8,9 Functional studies suggest that this variant is a polymorphism, which appears to have no major effect on p16 function. 10,11 Nevertheless, the A148T change has been found to be overrepresented in melanoma kindreds (3%) in comparison to the general population (1.8%). 12 In our population-based study, we found it to be associated with a significant increase in the risk of melanoma development (OR, 2.5; p 5 0.0003). We also observed that the A148T heterozygous carrier population was more likely to have a first-degree relative with cancer of any type compared to the non-carrier population: 57% versus 36%, respectively. 13 In our latest study, we reported significant overrepresentation of the A148T among breast cancer patients. 14 To determine whether this A148T change can be associated with an increased risk of malignancies at different sites of origin, we genotyped a series of 3,583 unselected cancer cases and compared the frequency of the change observed in this population to 3,000 controls in Poland. In this study, we examined eleven types of cancer, including seven of the most common in Poland, which represen...

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

Backgroud: Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers. Methods:In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFα) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls). Results:Of the six genes only one polymorphism in TNFα(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFα -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFα -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs). Conclusion:The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.