N-acetyltransferase 2 genotype in colorectal cancer and selective gene retention in cancers with chromosome 8p deletions

Abstract

Background-Genetic polymorphisms in N-acetyltransferase (NAT2) can change the normally fast acetylation of substrates to slow acetylation, and have been associated with the development of some cancers. The NAT2 locus may also suVer dysregulation during cancer progression, as the gene resides on chromosome 8p22, a region which is frequently deleted in colorectal cancer. Subjects and Methods-A polymerase chain reaction based method was used to determine NAT2 genotype in 275 patients with colon cancer and 343 normal control DNAs. Within the cancer group, 65 cases known to contain deletions in chromosome 8p were examined for loss of heterozygosity at the NAT2 locus. Results-Overall, there was no statistical diVerence in frequency or distribution of NAT2 alleles and genotype between colon cancer and control groups. There was a significant association between the slow acetylation genotype and early age of onset. NAT2 genotype did not vary with other clinical features of colon cancer, which included Dukes's stage, site of tumour, and sex. Of 48 informative cases, only three (6%) showed loss of heterozygosity, indicating that the NAT2 locus is not commonly deleted in colorectal cancer. This suggests that NAT2 is retained during the process of allele loss possibly because of its proximity to a gene necessary for cell viability. Conclusions-NAT2 does not play a major role in colorectal cancer risk, but may influence risk in some age groups. The nature of the loss of heterozygosity at the chromosome 8p site is complex and is worthy of further study. (Gut 1997; 41: 229-234)

N-acetyl transferase 1: two polymorphisms in coding sequence identified in colorectal cancer patients

“…The polymorphic status of the N-acetyltransferase 2 gene in these cancer and control groups was determined previously (Hubbard et al, 1997 …”

“…Polymorphisms of NAT2 that result in slow acetylation of metabolites have been associated with bladder cancer (Risch et al, 1995) and, conversely, fast acetylators may be more common in colorectal cancer and some types of breast cancer (Lang et al, 1986;Agundez et al, 1995). However these associations are weak and are not supported by all studies (Bell et al, 1995a;Hubbard et al, 1997).A potentially confounding factor in these assessments is the contribution of NATI, a closely related enzyme that shares some substrate specificity with NAT2 (Hein et al, 1992), which is expressed at higher levels than NAT2 in colonic epithelial cells (Turesky et al, 1991). Recent studies have shown that NATI is also polymorphic and 15 variants have been detected in animal and human gene sequences Weber and Vatsis, 1993;Grant et al, 1997).…”

“…Polymorphisms of NAT2 that result in slow acetylation of metabolites have been associated with bladder cancer (Risch et al, 1995) and, conversely, fast acetylators may be more common in colorectal cancer and some types of breast cancer (Lang et al, 1986;Agundez et al, 1995). However these associations are weak and are not supported by all studies (Bell et al, 1995a;Hubbard et al, 1997).…”

Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk

“…Indeed only one study involvin2 allelic loss of NAT2 has been published. and it was performed in colon cancer (Hubbard et al 1997). …”

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

“…However, results from a number of studies show only weak and inconsistent associations with disease susceptibility. N-acetyltransferase 2 (NAT-2) polymorphism may be implicated in susceptibility to colon cancer (Lang et al, 1986;Wohlleb et al, 1990;Illett et al, 1994;Probst-Hensch et al, 1995), but there is evidence that its relationship may be by linkage with other genes rather than causally (Hubbard et al, 1997).We have used a polymerase chain reaction (PCR) strategy to investigate whether polymorphisms in the microsomal epoxide hydrolase gene (mEPHX) (Hassett et al, 1994) have any relationship to colon cancer. The enzyme is expressed in many tissues, including colon and liver.…”