Prevalence of the APC E1317Q variant in colorectal cancer patients

doi:10.1016/S0304-3835(99)00360-2

Cancer Letters

Volume 149, Issues 1–2, 28 February 2000, Pages 203-206

https://doi.org/10.1016/S0304-3835(99)00360-2 Get rights and content

Abstract

The notion that some common variants of APC might confer an increased colorectal tumour risk is supported by studies of the I1307K polymorphism. Recently it has been proposed that the E1317Q variant is also associated with an increased risk. We have studied the prevalence of E1317Q in 364 colorectal cancer patients and in 290 controls. Two patients were shown to possess E1317Q. Neither had a family history of colorectal cancer or co-existent adenomatous polyps. Two controls also carried E1317Q. This finding suggests that E1317Q is unlikely to be associated with anything more than a moderate increase in risk of colorectal cancer.

Introduction

Familial adenomatous polyposis (FAP; MIM 175 100) is an autosomal dominant disorder predisposing to early onset colorectal cancer (CRC), secondary to florid colorectal adenomas. The classical form of FAP is caused by germ-line truncating mutations in APC [1] between approximately codon 168 (exon 4) and codon 1680 (exon 15) [2]. A variant of FAP, attenuated adenomatous polyposis coli, is characterised by less extensive polyposis and pronounced family histories of colorectal cancer. Truncating mutations in APC in these individuals may be found in the 5′ and 3′ regions of the gene [3], [4] as well as exon 9 [5].

A number of polymorphisms in APC have been documented, but because they are not expected to alter the predicted protein structure, they have not generally been considered to be pathogenic. However, a missense variant of APC in exon 15G (3920T–A; I1307K) has been shown to be associated with a 1.9-fold increase in colorectal cancer risk in Ashkenazim (95% CI: 1.2–2.8), combined data from [6] and [7]. Laken et al. [7] considered that this variant acted by a novel mechanism; that is by acting as a form of premutation, predisposing to somatic mutations at APC.

It is conceivable that other subtle or unconventional mutations in APC may be present which increase the risk of colorectal tumours. In a recent study of patients with multiple adenomas Frayling et al. [8] suggested that the E1317Q variant is associated with an increased risk of colorectal tumours. To assess this proposition we have examined the prevalence of the E1317Q variant in 364 colorectal cancer patients and 290 controls.

Section snippets

Patient selection

EDTA-venous blood samples were obtained from patients with histologically proven colorectal adenocarcinoma, diagnosed before age 55. Consecutive patients were ascertained through three Cancer Registries within the UK (Thames, Bristol and Wessex). Family histories of cancer in relatives were collected from all patients using a previously validated questionnaire. To establish a control group, blood samples were obtained from the spouses of patients. Samples and data were all collected with

Results

Three hundred and sixty-four patients and 290 healthy controls were studied. The mean age at diagnosis of colorectal cancer in the patients was 47.2 years (SD 6.70). Forty-six percent of cases were male. Fifty-nine percent of cases had colonic cancers. The average age of controls was 53.1 (SD 9.08) and 47% were male. None of the patients had clinical features indicative of classical FAP. Based upon the number of cases and controls analysed, this study has 80% power to detect a two-fold increase

Discussion

The idea that polymorphic variants of the high penetrance cancer predisposition genes might confer more modest risks is an attractive hypothesis. There is evidence for this notion since the I1307K variant in APC has been shown to be associated with an increased risk [6], [7], [8], [11].

Frayling et al. [8] have recently proposed that in addition to I1307K the E1317Q variant may also confer an increased risk of colorectal tumours. This suggestion follows from the observation that of a group of

Acknowledgments

We are grateful to the patients and individuals that took part in this study. S.P. is in receipt of a clinical training fellowship from the Institute of Cancer Research-Royal Marsden Trust. J.S. and G.C. are funded by the CRC.

References (13)

L Spirio et al.
Alleles of the APC gene: an attenuated form of familial polyposis
Cell
(1993)
C Soravia et al.
Genotype–phenotype correlations in attenuated adenomatous polyposis coli
Am. J. Hum. Gen.
(1998)
C Beroud et al.
APC gene: database of germ-line and somatic mutations in human tumors and cell lines
Nucleic Acids Res.
(1996)
Y Miyoshi et al.
Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene
Hum. Mol. Genet.
(1992)
R.B van der Luijt et al.
Germline mutations in the 3-prime part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli
Hum. Genet.
(1996)
T Woodage et al.
The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews
Nat. Genet.
(1998)

There are more references available in the full text version of this article.

Cited by (38)

The impact of APC polymorphisms on the transition from polyps to colorectal cancer (CRC)
2020, Gene
Citation 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.
The purpose of this study was to investigate the function of APC polymorphisms (D1822V and E1317Q) on the transition from polyps to colorectal cancer (CRC).
259 patients with polyps were included in the study. APC polymorphisms were genotyped via polymerase chain reaction (PCR) and subsequent sequencing. χ² test was performed to analyze the relationship of APC polymorphisms or CRC occurrence with clinical features. COX regression was used to find out risk factors for CRC. Hazard ratio (HR) and 95% confidence interval (CI) represented the risk of CRC.
Clinical information on sex, regular physical activity, smoking history, alcohol use and polyps types was recorded. Neither D1822V nor E1317Q polymorphism was associated with these factors. In following analysis, we found significant difference in the frequency of males between CRC and non-CRC patients (87.4% vs. 58.7%, P < 0.001). Distinct difference in the distribution of D1822V polymorphism was also observed between CRC and non-CRC patients (P = 0.001). In COX analysis, sex was identified as a risk factor for transition from polyps to CRC (HR = 2.442, 95%CI = 1.281–4.654). D1822V polymorphism tended to inhibit the transition process (HR = 0.286, 95%CI = 0.170–0.480). However, E1317Q seemed to have no significant effect on this process (HR = 1.042, 95%CI = 0.676–1.606).
In a word, APC D1822V polymorphism has strong effect on the transition from polyps to CRC.
ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)
2014, Genetics in Medicine
Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome—with extracolonic features—and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir–Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.
Genet Med16 1, 101–116.
Increased variance in germline allele-specific expression of APC associates with colorectal cancer
2012, Gastroenterology
Citation Excerpt :
The novel intronic variants were not predicted to have any effects on splicing or transcription. The missense variant rs1801166 (p.Glu1317Gln, commonly designated E1317Q), whose association with cancer is controversial,32,33 was detected at a relatively high frequency in sequenced cases with ASE (2 of 23) relative to all cases and to controls (Table 3), but our sample size does not allow us to draw conclusions regarding its association with disease. Of the 23 SNPs initially genotyped, only 8 were analyzed for association with ASE values and variances after excluding variants that were monomorphic or near-monomorphic (minor allele frequency, < 0.03) (Supplementary Table 5).
Germline variations in allele-specific expression (ASE) are associated with highly penetrant familial cancers, but their role in common sporadic cancers is unclear. ASE of adenomatous polyposis coli (APC) is associated with pathogenesis of familial adenomatous polyposis. We investigated whether moderate variations in ASE of APC contribute to common forms of colorectal cancer (CRC).
Denaturing high-performance liquid chromatography was used to analyze germline ASE of APC in blood samples from patients with CRC (cases, n = 53) and controls (n = 68). Means, medians, and variances of ASE were compared. Variants in the APC gene region also were analyzed.
The distribution of ASE differed significantly between groups; cases had significantly larger amounts of variance than controls (P = .0004). Risk for CRC increased proportionally with the degree of deviation from the mean. The odds ratio for individuals with levels of ASE that deviated more than 1 standard deviation from the mean was 3.97 (95% confidence interval, 1.71–9.24; P = .001); for those with levels greater than 1.645 standard deviations, the odds ratio was 13.46 (95% confidence interval, 1.76–609.40; P = .005). Sequence analysis revealed that a patient with a high level of ASE who did not have a family history of CRC carried a nonsense mutation in APC (p.Arg216X). Genotype analysis of APC associated multiple single-nucleotide polymorphisms with ASE values and/or variance among cases, but not controls. Cis variants, therefore, might account for some of the variance in ASE of APC.
Patients with CRC have a larger variance in germline levels of ASE in APC than controls; large distances from the mean ASE were associated with risk for common forms of CRC.
Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk
2010, European Journal of Cancer
Citation 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
While germline mutations in the adenomatous polyposis coli (APC) gene cause the hereditary colon cancer syndrome (familial adenomatous polyposis (FAP)), the role of common germline APC variants in sporadic adenomatous polyposis remains unclear. We studied the association of eight APC single nucleotide polymorphisms (SNPs), possibly associated with functional consequences, and previously identified gene–environment (dietary fat intake and hormone replacement therapy (HRT) use) interactions, in relation to advanced colorectal adenoma in 758 cases and 767 sex- and race-matched controls, randomly selected from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma of the distal colon; controls, a negative sigmoidoscopy. We did not observe an association between genotypes for any of the eight APC SNPs and advanced distal adenoma risk (P_{global gene-based} = 0.92). Frequencies of identified common haplotypes did not differ between cases and controls (P_{global haplotype test} = 0.97). However, the risk for advanced distal adenoma was threefold higher for one rare haplotype (cases: 2.7%; controls: 1.6%) (odds ratio (OR) = 3.27; 95% confidence interval (CI) = 1.08–9.88). The genetic association between D1822V and advanced distal adenoma was confined to persons consuming a high-fat diet (P_interaction = 0.03). Similar interactions were not observed with HRT use. In our large, nested case-control study of advanced distal adenoma and clinically verified adenoma-free controls, we observed no association between specific APC SNPs and advanced adenoma. Fat intake modified the APC D1822V-adenoma association, but further studies are warranted.
Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant
2009, Annals of Oncology
Citation Excerpt :
Whether the risk of colorectal neoplasia associated with E1317Q may be unique to Sephardic Jewish carriers is unknown; however, the positive findings of Hahnloser et al. [14] (likely few Sephardic Jews) and the negative findings of Rozek et al. [20] (approximately one-third of Sephardic Jews) go against this. Several groups have evaluated the risk of CRCs and/or adenomas associated with APC E1317Q in a case–control or case series format, but most have identified fewer than five carriers among case and/or control populations [8,10–13,15–19, 24]. Lamlum et al. [25] reported the strongest association to date in a select population with multiple adenomas (3–96 adenomas; OR 11.17, 2.30–54.3); results of other studies examining subjects with multiple adenomas (≥3 adenomas) have been nonsignificant but suggestive of an increased risk (OR 2.0 and RR 1.3) [17, 19.]
Reports of the risk of colorectal neoplasia associated with a variant of the adenomatous polyposis coli (APC E1317Q) gene are conflicting. Using a case–control design, we investigated this relationship within a clinic-based cohort followed through the Integrated Cancer Prevention Center and the Tel-Aviv Sourasky Medical Center.
All study subjects were tested for the APC E1317Q variant at enrollment. Subjects underwent colonoscopic evaluation (±biopsy and/or polypectomy) and had cancer history and colorectal neoplasia risk factors assessed. The crude and adjusted risks of neoplasia associated with the E1317Q variant were calculated.
The prevalence of the E1317Q variant was 1.4% in the entire study sample and 3.2% in Sephardic Jews. E1317Q was more prevalent among cases: 15 of 458 (3.3%) cases were carriers compared with 11 of 1431 (0.8%) controls [odds ratio (OR) 4.4, 95% CI 2.0–9.6]. When stratified by neoplasia type, adenoma risk was significantly elevated in carriers (OR 4.1, 95% CI 1.8–9.4) but colorectal cancer risk was not (OR 2.1, 95% CI 0.8–5.3). After adjustment, the E1317Q variant remained a significant predictor of colorectal adenoma (OR 4.6, 95% CI 2.0–10.8).
The APC E1317Q variant is associated with colorectal neoplasia, particularly colorectal adenomas, but further studies are still needed. Variant prevalence is elevated in Sephardic Jews.
Genetic testing for inherited colon cancer
2005, Gastroenterology
The genes associated with each of the inherited syndromes of colon cancer have now been identified, and genetic testing is available for diagnosis. These syndromes include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and, possibly, Cowden’s syndrome. Clinical genetic testing approaches have been developed for each of these syndromes and are now a part of accepted clinical care. Disease-causing mutations can be found in the majority of families affected with one of the inherited syndromes, and, most importantly, once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near 100% accuracy. Cancer screening and management in syndrome families is then based on the results of genetic testing. For the physician to order and properly interpret genetic tests, a basic understanding of the types of mutations that lead to inherited disease and the methods for detecting them is vital. These issues will be presented. Additional clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing, both of which will also be reviewed. Often the most difficult aspect of genetic testing is deciding which patients and families should undergo the testing. Furthermore, this issue is quite specific for each of the syndromes. Thus, following presentation of general principles of selection for genetic testing, a detailed approach for identifying persons who should undergo testing for each of the individual syndromes will be given, together with relevant descriptions of the syndromes. Finally, the ongoing work to discover new and possibly more common but less penetrant colon cancer susceptibility genes that cause common familial colon cancer will be presented.

View all citing articles on Scopus

View full text

Article preview

Cancer Letters

Abstract

Introduction

Section snippets

Patient selection

Results

Discussion

Acknowledgments

References (13)

Alleles of the APC gene: an attenuated form of familial polyposis

Cell

Genotype–phenotype correlations in attenuated adenomatous polyposis coli

Am. J. Hum. Gen.

APC gene: database of germ-line and somatic mutations in human tumors and cell lines

Nucleic Acids Res.

Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene

Hum. Mol. Genet.

Germline mutations in the 3-prime part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli

Hum. Genet.

The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews

Nat. Genet.

Cited by (38)

The impact of APC polymorphisms on the transition from polyps to colorectal cancer (CRC)

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

Increased variance in germline allele-specific expression of APC associates with colorectal cancer

Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk

Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant

Genetic testing for inherited colon cancer