APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients

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Abstract

Recently, a germ line mutation of the APC gene, I1307K, was discovered in a subset of Ashkenazi jews. The mutation involves an amino acid exchange and creates a tract consisting of eight contiguous adenosine residues believed to cause hypermutability in this region. Another germ line missense variant, E1317Q, not restricted to a certain ethnic population, could functionally alter the protein. These APC variants have been linked with increased colorectal cancer risk in several studies. However, they have not yet been investigated in Swedish colorectal cancer patients. Thus, our aim was to investigate the prevalence of I1307K and E1317Q in Swedish colorectal cancer patients in order to determine if these genetic variants are important predisposing factors to colorectal cancer in this population. To this end, sequence analysis was carried out of the APC gene in order to identify any I1307K and E1317Q variants in 106 unselected cases and 88 hereditary/familial colorectal cancer cases including 22 cases of hereditary non-polyposis colorectal cancer (HNPCC) fulfilling the Amsterdam criteria. Out of a total of 194 cases examined, we did not find any variants. It seems that these alterations are rare or absent in the Swedish population.

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.

Section snippets

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.

References (14)

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