APC I1307K Allele Research Articles

Position statement of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) on APC I1307K and cancer risk

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in...

The APC I1307K allele conveys a significant increased risk for cancer.

This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is ∼ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan.

Su1945 The APC I1307k Allele Conveys Different Risks for Cancer in Men and Women

Su1945 The APC I1307k Allele Conveys Different Risks for Cancer in Men and Women

Su1225 The Association Between the APC I1307K Allele and Colorectal and Non-Colorectal Cancer Risk

Su1225 The Association Between the APC I1307K Allele and Colorectal and Non-Colorectal Cancer Risk

How the I1307K adenomatous polyposis coli gene variant contributes in the assessment of risk of colorectal cancer, but not stomach cancer, in a Turkish population

Germline and somatic truncating mutations of the adenomatous polyposis coli gene ( APC) are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine–lysine polymorphism at codon 1307 ( I1307K) of the APC gene has been identified in 6–7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, a cohort of unselected Turkish subjects with stomach or colorectal cancer (or both) was analyzed for the APC I1307K polymorphism. Genomic DNA was extracted from patients by obtaining all stomach and colon malign polipose tissues using nuclei lysis methods. Detection of the I1307K mutation was performed using the commercial Pronto APC kit according to the manufacturer's instructions. The APC I1307K allele was identified in 7 of 57 stomach carcinoma patients (12.3%; P > 0.05) and 30 of 56 colon carcinoma patients (53.6%; P < 0.05) using antigen–anticor interaction methods. Comparing the frequencies of the two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.9 for colorectal neoplasia. Furthermore, APC I1307K carriers had greater numbers of adenomas and colorectal cancers per patient than noncarriers. The conclusion is that the APC I1307K variant leads to increased adenoma formation and colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for Turkish people expected to harbor this allele, and genetic testing in the long term may significantly promote colorectal cancer prevention in this population.

Colorectal tumourigenesis in carriers of the APC I1307K variant: lone gunman or conspiracy?

The APC I1307K allele is believed to predispose to multiple colorectal tumours because the change at the nucleotide level-A(3)TA(4) to A(8)-creates a hypermutable site. Slippage of the A(8) tract undoubtedly occurs more often than expected in the tumours of I1307K carriers, but many of these tumours do not harbour changes at this site. Outside the A(8) tract, the tumours of I1307K carriers appear to harbour fewer somatic frameshift mutations than expected. There is inconsistent evidence as to whether or not I1307K confers an increased risk of colorectal cancer. Most I1307K patients and families who have undergone analysis of somatic APC mutations have been highly selected. It is therefore possible that many APC I1307K carriers with multiple adenomas have a susceptibility to tumours additional to that resulting from the A(8) tract.

"Hot spots" can burn you.

Abstract Germline mutation in the APC gene predisposes to the rare familial adenomatous polyposis syndrome, in which hundreds to thousands of adenomatous polyps develop in the large intestine, as well as early-onset colorectal cancers. APC gene mutations are also found in approximately 80% of all sporadic colon cancers and appear to be the earliest mutations in the adenoma-carcinoma sequence (1) . Once the APC gene is lost through mutations in both copies or alleles and adenoma formation is complete, mutations in other colon cancer genes are necessary to continue the transformation to carcinoma. Recently, a polymorphism (variations of a gene that are found in >1% of the population) in the APC gene, I1307K, was found to confer a nearly 2-fold risk of colon cancer in individuals heterozygous for the allele (2) . The I1307K APC polymorphism is rarely found in the general population, but occurs in the Ashkenazi Jew population with carrier frequencies ranging from 5.9% to 7.3%. The I1307K polymorphism is a T-to-A transversion at nucleotide 3920. Laken et al. found that the I1307K allele is frequently mutated or lost in colonic tumors, suggesting that the nonmutated allele does not directly participate in the tumorigenic process, but may indirectly cause an unstable, hypermutable sequence or “hot spot” in an adjacent portion of the APC gene. This may lead to mutations and deletions at nearby sequences in the APC allele, which may account for the absence of the I1307k allele in cancers arising in carriers of the allele. Thus, this polymorphism may ultimately lead to inactivation of the APC allele through deletions on the same chromosome. Stern et al. sought to determine any predisposition to colonic adenoma formation associated with being heterozygous for eh I1307K APC polymorphism. To accomplish this, 3540 households in the Jewish community of Ottawa were sent invitations to participate as well as family questionnaires. Two hundred forty-two respondents with personal or family histories of colorectal cancer were selected, and nearly 80% underwent colonoscopy. All had blood drawn for detection of the I1307K allele of the APC gene using an allele-specific polymerase chain reaction assay, with two previously known heterozygotes for APC I1307K used as controls. The participants were divided into three subgroups: I) 22 participants (9%) having personal histories of colorectal cancer; II) 11 participants (5%) having personal histories of extracolonic cancer including melanoma (three), breast (four), skin (two), and bladder (two); and III) the remaining 209 participants with family histories but no personal histories of cancer. Results: The I1307K allele was found in 25/242 participants (10.3%). All were heterozygous for I1307K. Those with personal histories of any type of cancer (groups I and II) were 2–3 times as likely to carry the mutation as those with no cancer history (I = 27.3%, II = 18.2%, III = 8.1%). The difference between those with personal histories of colorectal cancer (group I) and those with no personal histories of cancer (group III) was statistically significant. No difference was seen regarding gender or number of first-degree relatives with colorectal cancer. Polyps were found in 44/189 participants (23%) who agreed to colonoscopy. There was no statistically significant difference in adenoma development between the groups. Group I had six patients decline colonoscopy, but in the 16 who underwent exams, only two lesions (solitary adenomas) were found, in two participants. Neither carried the I1307K allele, and none of the five I1307K carriers had polyps. Although 6% of gene carriers younger than 57 from all groups developed polyps, all were diminutive and hyperplastic. To evaluate the role of the APC I1307K allele in those with no personal histories of colorectal cancer groups II and III were combined. There was no difference between I1307K allele carriers and noncarriers with regard to all polyps found (23% in both groups), adenomas (11.8% and 12.8%), or hyperplastic polyps (6% and 8%). Importantly, 10/12 patients (83%) with multiple polyps and all four with tubovillous adenomas were noncarriers. Polyp size, number, location, histological subtype, and early development of adenomas were not correlated with carrier status.

“Hot spots” can burn you

Germline mutation in the APC gene predisposes to the rare familial adenomatous polyposis syndrome, in which hundreds to thousands of adenomatous polyps develop in the large intestine, as well as early-onset colorectal cancers. APC gene mutations are also found in approximately 80% of all sporadic colon cancers and appear to be the earliest mutations in the adenoma-carcinoma sequence (1). Once the APC gene is lost through mutations in both copies or alleles and adenoma formation is complete, mutations in other colon cancer genes are necessary to continue the transformation to carcinoma. Recently, a polymorphism (variations of a gene that are found in >1% of the population) in the APC gene, I1307K, was found to confer a nearly 2-fold risk of colon cancer in individuals heterozygous for the allele (2). The I1307K APC polymorphism is rarely found in the general population, but occurs in the Ashkenazi Jew population with carrier frequencies ranging from 5.9% to 7.3%. The I1307K polymorphism is a T-to-A transversion at nucleotide 3920. Laken et al. found that the I1307K allele is frequently mutated or lost in colonic tumors, suggesting that the nonmutated allele does not directly participate in the tumorigenic process, but may indirectly cause an unstable, hypermutable sequence or “hot spot” in an adjacent portion of the APC gene. This may lead to mutations and deletions at nearby sequences in the APC allele, which may account for the absence of the I1307k allele in cancers arising in carriers of the allele. Thus, this polymorphism may ultimately lead to inactivation of the APC allele through deletions on the same chromosome. Stern et al. sought to determine any predisposition to colonic adenoma formation associated with being heterozygous for eh I1307K APC polymorphism. To accomplish this, 3540 households in the Jewish community of Ottawa were sent invitations to participate as well as family questionnaires. Two hundred forty-two respondents with personal or family histories of colorectal cancer were selected, and nearly 80% underwent colonoscopy. All had blood drawn for detection of the I1307K allele of the APC gene using an allele-specific polymerase chain reaction assay, with two previously known heterozygotes for APC I1307K used as controls. The participants were divided into three subgroups: I) 22 participants (9%) having personal histories of colorectal cancer; II) 11 participants (5%) having personal histories of extracolonic cancer including melanoma (three), breast (four), skin (two), and bladder (two); and III) the remaining 209 participants with family histories but no personal histories of cancer. Results: The I1307K allele was found in 25/242 participants (10.3%). All were heterozygous for I1307K. Those with personal histories of any type of cancer (groups I and II) were 2–3 times as likely to carry the mutation as those with no cancer history (I = 27.3%, II = 18.2%, III = 8.1%). The difference between those with personal histories of colorectal cancer (group I) and those with no personal histories of cancer (group III) was statistically significant. No difference was seen regarding gender or number of first-degree relatives with colorectal cancer. Polyps were found in 44/189 participants (23%) who agreed to colonoscopy. There was no statistically significant difference in adenoma development between the groups. Group I had six patients decline colonoscopy, but in the 16 who underwent exams, only two lesions (solitary adenomas) were found, in two participants. Neither carried the I1307K allele, and none of the five I1307K carriers had polyps. Although 6% of gene carriers younger than 57 from all groups developed polyps, all were diminutive and hyperplastic. To evaluate the role of the APC I1307K allele in those with no personal histories of colorectal cancer groups II and III were combined. There was no difference between I1307K allele carriers and noncarriers with regard to all polyps found (23% in both groups), adenomas (11.8% and 12.8%), or hyperplastic polyps (6% and 8%). Importantly, 10/12 patients (83%) with multiple polyps and all four with tubovillous adenomas were noncarriers. Polyp size, number, location, histological subtype, and early development of adenomas were not correlated with carrier status.

Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency.

Inherited BRCA2 mutations predispose individuals to breast cancer and increase risk at other sites. Recent studies have suggested a role for the APC I1307K allele as a low-penetrance breast cancer susceptibility gene that enhances the phenotypic effects of BRCA1 and BRCA2 mutations. To model the consequences of inheriting mutant alleles of the BRCA2 and APC tumor suppressor genes, we examined tumor outcome in C57BL/6 mice with mutations in the Brca2 and Apc genes. We hypothesized that if the Brca2 and Apc genes were interacting to influence mammary tumor susceptibility, then mammary tumor incidence and/or multiplicity would be altered in mice that had inherited mutations in both genes. Female and male offspring treated with a single IP injection of 50 mg/kg N-ethyl-N-nitrosourea (ENU) at 35 days of age developed mammary adenoacanthomas by 100 days of age. The female Apc-mutant and Brca2/Apc double-mutant progeny had mean mammary tumor multiplicities of 6.7+/-2.8 and 7.2+/-2.7, respectively, compared to wild-type and Brca2-mutant females, which had mean mammary tumor multiplicities of 0.1+/-0.4 and 0.3+/-0.5, respectively. Female ENU-treated Apc-mutant and Brca2/Apc double heterozygotes were also susceptible to premature ovarian failure. Thus, the inheritance of an Apc mutation predisposes ENU-treated female and male mice to mammary tumors and, in the case of female mice, to ovarian failure. These results indicate that mammary tumor development in Apc-mutant mice can progress independently of ovarian hormones. The Apc mutation-driven phenotypes were not modified by mutation of Brca2, perhaps because Brca2 acts in a hormonally dependent pathway of mammary carcinogenesis.

Body mass, age, and the APC I1307K allele in Ashkenazi Jewish prostate cancer patients

The I1307K mutation of the adenopolyposis coli gene (APC), located on chromosome 5q21–q22, is associated with an increased risk of cancer in Ashkenazi Jews. In the present study, we analyzed age and body mass of Ashkenazi Jewish prostate cancer patients, with and without the APC I1307K mutation. Participants in our study were found through urology and radiation oncology clinics, and all eligible patients were asked to take part. A familial history was obtained by interview or self-report questionnaire. Histological confirmation of diagnosis was obtained for all subjects. The I1307K allele of the APC gene was detected by amplification of lymphocyte DNA from peripheral blood according to standard polymerase chain reaction (PCR) and dot blot procedures. We studied 135 Ashkenazi Jewish men with prostate cancer. The youngest was 49, the oldest 80, average age 68 ± 6.88 (mean ± SD). The older patients carrying the wild type APC allele tended to have a lower body mass than the younger ones (r = −.27, P = .002). Of 71 patients under 70 years old, 65 carried the wild type APC allele, and had a body mass index of 28.7 ± 4.23 kg/m 2. The six men under age 70 carrying the I1307K APC allele had a body mass index of 26.87 ± 1.44 kg/m 2. The difference in body mass index of the two groups is significant ( P = .032, t test for unequal variance). Increased body mass is a prostate cancer risk factor, and hereditary prostate cancer is associated with younger patients. Therefore, our finding, that patients under age 70 carrying the I1307K allele are significantly thinner than those carrying the wild type allele, suggests that the APC I1307K allele is also a prostate cancer risk factor. Our results are in accord with other studies indicating that APC mutations increase the risk of prostate cancer.

Ligase-based detection of mononucleotide repeat sequences.

Up to 15% of all colorectal cancers are considered to be replication error positive (RER(+)) and contain mutations at hundreds of thousands of microsatellite repeat sequences. Recently, a number of intragenic mononucleotide repeat sequences have been demonstrated to be targets for inactivating genes in RER(+)colorectal tumors. In this study, thermostable DNA ligases were tested for the ability to detect alterations in microsatellite sequences in colon tumor samples. Ligation profiles on mononucleotide repeat sequences were determined for four related thermostable DNA ligases, Thermus thermophilus ( Tth ) ligase, Thermus sp. AK16D ligase, Aquifex aeolicus ligase and the K294R mutant of the Tth ligase. While the limit of detection for point mutations was one mutation in 1000 wild-type sequences, the ability to detect a single base deletion in a 10 base mononucleotide repeat was one mutation in 100 wild-type sequences. Furthermore, the misligation error increased exponentially as the length of the mono-nucleotide repeat increased, and was 10% of the correct signal for a 19 base mononucleotide repeat. A fluorescent ligase-based assay [polymerase chain reaction/ligase detection reaction (PCR/LDR)] correlated with results obtained using a radioactive assay to detect instability within the TGF-beta Type II receptor gene. PCR/LDR was also used to detect the APCI1307K mononucleotide repeat allele which has a carrier frequency of 6.1% in Ashkenazi Jewish individuals. In a blind study, 30 samples that had been typed for the presence of the APCI1307K allele were tested. The PCR/LDR results correlated with those obtained using sequencing and allele-specific oligonucleotide hybridization for 16 samples carrying the mutation and 13 wild-type samples. Ligation assays that characterize mononucleotide repeats can be used to rapidly detect somatic mutations in tumors, and to screen for individuals who have a hereditary predisposition to develop colon cancer.

Inherited Colorectal Polyposis and Cancer Risk of the APC I1307K Polymorphism

Germ-line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine-->lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and.or colorectal cancer, for the APC I1307K polymorphism. The APC I1307K allele was identified in 48 (10.1%) of 476 patients. Compared with the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.5-1.7 for colorectal neoplasia (both P=.01). Furthermore, compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P=.03), as well as a younger age at diagnosis. We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for the 360,000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colorectal cancer prevention in this population.