Carrier rate of APC I1307K is not increased in inflammatory bowel disease patients of Ashkenazi Jewish origin

Abstract

Colorectal cancer (CRC) occurs with an increased incidence in individuals with chronic inflammatory bowel disease (IBD) of the colon. Recent data suggest that a family history of colorectal cancer is an independent risk factor for CRC in IBD, an observation that implies that genetic factors are relevant to the development of CRC in this context. Among the genetic defects associated with CRC, the APC I1307K mutation has been detected nearly exclusively in individuals of Ashkenazi Jewish (AJ) origin, occurring in 6%-7% of the AJ general population and in 10%-28% of AJ with a either a personal or family history of CRC or adenomatous polyps. These findings, together with the increased incidence of IBD in AJ, prompted the current analysis of the contribution of the APC I1307K variant of CRC in AJ IBD patients. APC I1307K carrier frequencies were determined in 306 AJ individuals affected with IBD and 308 of their unaffected relatives ascertained from a family collection obtained for the identification of IBD susceptibility genes. Prevalence of the I1307K variant was not significantly different among individuals with IBD, Crohn's disease, ulcerative colitis, and unaffected relatives (6.9%, 7.6%, 4.7%, and 6.2%, respectively), and the mutation was detected in only one of five IBD-affected individuals with a diagnosis of CRC. These results reveal that IBD patients of AJ origin carry the APC I1307K variant at the same rate as individuals within the general AJ population. Lack of an increased APC I1307K carrier rate suggests that this mutation does not account for the increased CRC susceptibility associated with IBD.

Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia

“…Studies from various communities worldwide in which Ashkenazi Jews are concentrated have examined the occurrence of this genetic variant in Jewish Ashkenazi patients with breast carcinoma, ovarian carcinoma, and ulcerative colitis, because these diseases are more common in the Jewish people. 3, 19–24 Overall, no such associations with the I1307K variant were found other than a significant excess risk (OR, 1.5) in BRCA1 or BRCA2 breast carcinoma heterozygotes, a finding that the authors also felt did not justify clinical testing for I1307K 20. Our clinical findings are consistent with the characteristics of many other Ashkenazi Jewish diseases, which are mostly autosomal‐recessive disorders,25 for example, Gaucher disease, in which the asymptomatic heterozygous carrier rate in Ashkenazi Jews is 5.8%, but only a minority (10.3%) of homozygotes are actually symptomatic.…”

Genetic factors and colorectal cancer in Ashkenazi Jews

“…Ashkenazi Jews have an increased incidence of inflammatory bowel disease [22] affecting the large bowel, a known risk factor for developing colorectal cancer. In a study of 306 Ashkenazim with IBD, there was no difference in their carrier rate of the I1307K polymorphism (6.9%) compared to 308 of their unaffected relatives (6.2%) [23]. The incidence of I1307K in both is similar to that reported for the general Ashkenazi population [15,[24][25][26][27][28][29].…”

Colorectal Polyps in Carriers of the APC I1307K Polymorphism

“…1 Several studies have confirmed that the magnitude of risk of colorectal cancer conferred by this polymorphism is approximately 1.8 times the risk among noncarriers. [2][3][4][5][6][7][8] Some have looked at this polymorphism with regard to other disease groups such as inflammatory bowel disease 9 and multiple adenomas. 10-11 APC I1307K does not account for the increased risk of colorectal cancer in patients with inflammatory bowel disease, but it appears to be overrepresented among individuals with multiple adenomas.…”