APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients
Introduction
The APC gene, located at 5q21-22, is a tumour suppressor gene whose germ line mutations are classically associated with familial adenomatous polyposis (FAP), a risk factor for colorectal cancer. In most sporadic colorectal cancers, inactivating mutations, spread between codons 168 and 1680, are believed to be critical in the early stages of tumour development [1]. Recently, less penetrant germ line variants have gained attention as predisposing for cancer. The polymorphism most thoroughly investigated is a transversion from T to A at codon 1307 (I1307K), which creates a poly A (A8) tract and results in an amino acid exchange, lysine for isoleucine. The variant is believed to increase cancer susceptibility since it gives rise to an unstable hypermutable region of the gene, leading to truncating somatic mutations at adjacent sequences, although a direct functional effect on the protein is also possible since it gives rise to a charge change in a critical part of the APC molecule. It has been linked with increased colorectal cancer risk with odds ratios (ORs) of 1.9 2, 3, 4. The variant was found in 28% of Ashkenazi Jews with a family history for colorectal cancer, in 10% of Ashkenazi Jews with sporadic colorectal cancer and in 6% of Ashkenazi Jews without colorectal cancer, but not in 243 non-Jewish individuals without colorectal cancer [2]. Several other groups have looked for this APC variant in non-Jewish populations to evaluate if the I1307K allele is unique to Ashkenazi Jews, but with negative results 5, 6, 7. Only recently, Nathanson and colleagues [8] reported a non-Jewish woman of Italian descent, affected with breast and ovarian cancer and with a family history of colon cancer, who was heterozygotic for the I1307K allele. Another germ line missense variant in close proximity to I1307K (E1317Q) involves a mutation (G→C) which leads to a glutamic acid to glutamine substitution 5, 6, 9, 10. It has been suggested that this alteration contributes to a predisposition to colorectal adenoma and carcinoma in both Ashkenazi and non-Jewish populations but with low and variable penetrance [6].
Since there is no information about I1307K and E1317Q in the Swedish population, the aim of the present study was to investigate the prevalence of I1307K and E1317Q in Swedish colorectal cancer patients in order to identify whether these alleles predispose to colorectal cancer. We also wanted to investigate whether there is a difference in the frequency of the mutations between the hereditary/familial and sporadic forms of the disease. The study was accomplished by sequence analysis of the APC gene for I1307K and E1317Q in 194 Swedish colorectal cancer patients, including some with hereditary and familial colorectal cancers.
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Patients
The study included colorectal cancer patients from two separate groups. Fresh frozen normal colorectal tissue were received consecutively from 106 (55%) of unselected patients, whose family histories were unknown, diagnosed between the years 1984 to 1999 in the region of Linköping and Norrköping. Patients' sex, age, tumour site and Dukes' stage, were confirmed from surgical and pathological records. The grade of differentiation was scored by one of the authors as previously recommended 11, 12,
Results
Out of totally 194 cases examined, including 106 unselected cases and 88 hereditary/familial colorectal cancer cases including 22 cases of HNPCC, we did not find the APC germ line mutations I1307K or E1317Q.
Discussion
The results imply that neither I1307K nor E1317Q severely affect the risk of developing colorectal cancer in the Swedish population. Interestingly, in a Norwegian study of 210 colorectal cancer patients, and 183 breast cancer patients with and without a family history of cancer, no patient exhibited the allele I1307 K except for a colorectal cancer patient of Jewish descent. The prevalence was estimated to be <1% [7]. Our study supports their findings and it appears that the frequency of this
Acknowledgments
Supported by grants from the Swedish Cancer Foundation and FORSS.
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Cited by (21)
The genetic factors associated with Wnt signaling pathway in colorectal cancer
2020, Life SciencesCitation Excerpt :Generally, APC mutational analysis illustrated that most of the germline mutations found in FAP are nonsense proceeding to a truncated form of the protein [72]. Two exceptions of truncating mutations are germline missense mutations within the APC gene, including I1307K with a transversion from T to A at codon 1307 resulting to the substitution of lysine for isolysine, and E1317Q with a mutation of G to C leading to the conversion of glutamic acid to glutamine, both involved at a more CRC predisposition in Ashkenazi Jews [73]. In particular, some inactivating mutations in the APC gene account for HNPCC [74].
The impact of APC polymorphisms on the transition from polyps to colorectal cancer (CRC)
2020, GeneCitation Excerpt :Similar result was also observed in the study of Frayling et al (Lamlum et al., 2000). By contrast, Popat et al. found no significant difference in the frequency of E1317Q variant between CRC patients and healthy controls (0.6% vs. 0.7%) (Popat et al., 2000); which was supported by several studies (Evertsson et al., 2001; Figer et al., 2001). No positive result was obtained in our study for E1317Q polymorphism either.
Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk
2010, European Journal of CancerCitation Excerpt :There is a paucity of data on common genetic variants in the APC gene and colorectal adenoma risk. Previous studies31–43 have focused on four germline missense variants, i.e. APC I1307K, E1317Q, D1822V and G2502S, of which, APC I1307K32,44 and APC E1317Q31 are founder mutations in Ashkenazi Jews and have a rare prevalence (minor allele frequency (MAF) of <1%) in non-Hispanic Whites.33–36 In Askenazim, APC I1307K (MAF = 6%) is associated with risk of colon cancer without the corresponding polyposis seen in FAP patients32,44 and APC E1317Q31 is associated with colorectal tumours in some but not all studies.38,39
Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant
2009, Annals of OncologyCitation Excerpt :This study is the first to report an enrichment of the E1317Q variant in Sephardic Jews. Previous studies examining E1317Q prevalence have identified variable carrier rates in self-reported Jewish (1.1%–1.4% Ashkenazi men and women [12, 13]) and non-Jewish (0.0% Swedish [18] and Chinese [23]) control groups. A concentration of the E1317Q variant in Sephardic but not Ashkenazi Jews would indicate that this variant entered the population after the fragmentation of Central/Eastern European Jews (Ashkenazim) from the Sephardim.
APC gene loss of heterozygosity, mutations, E1317Q, and I1307K germ-line variants in sporadic colon cancer in Croatia
2004, Experimental and Molecular Pathology