Early Onset Colorectal Carcinoma Research Articles

Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg→Trp) ( 194Trp) and 399 (Arg→Gln) ( 399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73–9.40, and P=0.08 for 194Trp allele and OR=3.98, 95% CL 1.50–10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48–35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30–51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48–35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98–43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36–26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50–7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.

Author reply

We welcome the correspondence from Dr. Seruca and Dr. Sobrinho-Simões confirming our observation of a paucity of microsatellite instability in young patients with gastric adenocarcinoma.1 We recently studied gastric adenocarcinomas in 17 more young patients younger than 40 years from Braga, Portugal (unpublished data). A mutator phenotype suggestive of the hereditary nonpolyposis colorectal carcinoma syndrome2 was found in only one case (6%). However, low level microsatellite instability occurring in less than 29% of markers analyzed3 was detected in 6 more cases (35%). Although the significance of low frequency microsatellite instability is as yet undetermined, there may be subtle differences in the molecular pathology of gastric carcinoma occurring in young patients from relatively high and low risk populations that require exploration. The data reported so far suggest that the prevalence of a hereditary nonpolyposis colorectal carcinoma-associated mutator phenotype is lower in early onset gastric carcinoma than in early onset colorectal carcinoma.4 It remains to be determined whether or not the few early onset gastric carcinomas with a mutator phenotype harbor underlying DNA mismatch repair gene mutations. Jeremy D. Hayden B.Sc. M.B. Ch.B.*, Iain G. Martin M.D. F.R.C.S.*

Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review.

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Aldred Warthin's description of Family G a century ago. The phenotype features an excess of early onset colorectal carcinoma (CRC) with a propensity to involve the proximal colon, and a variety of extracolonic cancers, particularly carcinoma of the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis. The recent discovery that HNPCC patients carry germline mutations in DNA mismatch repair genes has engendered great interest in the syndrome. This is a description of HNPCC based on the authors' experience with more than 170 families and a review of the world literature. This review describes the genotypic and phenotypic features of HNPCC. The distinctive natural history of the syndrome is discussed in light of the recent discovery that ineffective DNA mismatch repair is the principal abnormality in affected individuals. Clinical and molecular genetic knowledge about HNPCC is now available to physicians, and should enable them to provide highly targeted surveillance and management for patients with a high cancer risk. Genetic counseling can prove lifesaving. The study of HNPCC will likely contribute to knowledge about the causes and control of common forms of cancer in the general population.

Hereditary nonpolyposis colorectal cancer (Lynch syndrome): An updated review

BACKGROUND Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Aldred Warthin's description of Family G a century ago. The phenotype features an excess of early onset colorectal carcinoma (CRC) with a propensity to involve the proximal colon, and a variety of extracolonic cancers, particularly carcinoma of the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis. The recent discovery that HNPCC patients carry germline mutations in DNA mismatch repair genes has engendered great interest in the syndrome. METHODS This is a description of HNPCC based on the authors' experience with more than 170 families and a review of the world literature. RESULTS This review describes the genotypic and phenotypic features of HNPCC. The distinctive natural history of the syndrome is discussed in light of the recent discovery that ineffective DNA mismatch repair is the principal abnormality in affected individuals. CONCLUSIONS Clinical and molecular genetic knowledge about HNPCC is now available to physicians, and should enable them to provide highly targeted surveillance and management for patients with a high cancer risk. Genetic counseling can prove lifesaving. The study of HNPCC will likely contribute to knowledge about the causes and control of common forms of cancer in the general population. Cancer 1997;78:1149-67.