Dataset Information

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

ABSTRACT:

Purpose

The aim of this study was to assess whether differences in frequency and phenotype of APC and MUTYH mutations exist among racially/ethnically diverse populations.

Methods

We studied 6,169 individuals with a personal and/or family history of colorectal cancer (CRC) and polyps. APC testing involved full sequencing/large rearrangement analysis (FS/LRA); MUTYH involved "panel testing" (for Y165C, G382D mutations) or FS/LRA performed by Myriad Genetics, a commercial laboratory. Subjects were identified as Caucasian, Asian, African American (AA), or other. Statistical tests included χ(2), Fisher's exact test, analysis of variance, and z approximation.

Results

Among participants, 17.5% had pathogenic APC mutations and 4.8% were biallelic MUTYH carriers. With regard to race/ethnicity, 18% were non-Caucasian, with >100 adenomas and younger ages at adenoma or CRC diagnosis (P < 0.0001) than Caucasians. The overall APC mutation rate was higher in Asians, AAs, and others as compared with Caucasians (25.2, 30.9, 24, and 15.5%, respectively; P < 0.0001) but was similar in all groups when adjusted for polyp burden. More MUTYH biallelic carriers were Caucasian or other than Asian or AA (5, 7, 2.7, and 0.3%, respectively; P < 0.0001). Among Caucasians, 5% were biallelic carriers identified by panel testing versus 2% identified by sequencing/large rearrangement analysis (LRA) (P = 0.002). Among non-Caucasians, 3% undergoing panel testing were biallelic carriers versus 10% identified by sequencing/LRA (P < 0.0002).

Conclusion

Non-Caucasians undergo genetic testing at more advanced stages of polyposis and/or are younger at CRC/polyp diagnosis. Restricted MUTYH analysis may miss significant numbers of biallelic carriers, particularly in non-Caucasians.

SUBMITTER: Inra JA

PROVIDER: S-EPMC4904772 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Publications

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

Inra Jennifer A JA Steyerberg Ewout W EW Grover Shilpa S McFarland Ashley A Syngal Sapna S Kastrinos Fay F

Genetics in medicine : official journal of the American College of Medical Genetics 20150115 10

<h4>Purpose</h4>The aim of this study was to assess whether differences in frequency and phenotype of APC and MUTYH mutations exist among racially/ethnically diverse populations.<h4>Methods</h4>We studied 6,169 individuals with a personal and/or family history of colorectal cancer (CRC) and polyps. APC testing involved full sequencing/large rearrangement analysis (FS/LRA); MUTYH involved "panel testing" (for Y165C, G382D mutations) or FS/LRA performed by Myriad Genetics, a commercial laboratory. ...[more]

PMID: 25590978

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Project description:ContextPatients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes.ObjectivesTo determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers.Design, setting, and participantsCross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses.Main outcome measurePrevalence of pathogenic mutations in APC and MUTYH genes.ResultsColorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses.ConclusionsAmong patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.

Project description:BackgroundTranscript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele-specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes.MethodsWe analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age. Patients were studied for germline alterations in both genes using dHPLC, MLPA and automated sequencing. APC and MUTYH mRNA expression levels were investigated by quantitative Real-Time PCR (qRT-PCR) analysis using TaqMan assay and by ASE assays using dHPLC-based primer extension.ResultsTwenty out of 49 patients showed germline mutations: 14 in APC gene and six in MUTYH gene. Twenty-nine patients did not show mutations in both genes. Results from qRT-PCR indicated that gene expression of both APC and MUTYH was reduced in patients analyzed. In particular, a significant reduction in APC expression was observed in patients without APC germline mutation vs control group (P < 0.05) while APC expression in the mutation carrier patients, although lower compared to control individuals, did not show statistical significance. On the other hand a significant reduced MUTYH expression was detected in patients with MUTYH mutations vs control group (P < 0.05). Altered ASE of APC was detected in four out of eight APC mutation carriers. In particular one case showed a complete loss of one allele. Among APC mutation negative cases, 4 out of 13 showed a moderate ASE. ASE of MUTYH did not show any altered expression in the cases analyzed. Spearman's Rho Test analysis showed a positive and significant correlation between APC and MUTYH genes both in cases and in controls (P = 0.020 and P < 0.001).ConclusionsAPC and MUTYH showed a reduced germline expression, not always corresponding to gene mutation. Expression of APC is decreased in mutation negative cases and this appears to be a promising indicator of FAP predisposition, while for MUTYH gene, mutation is associated to reduced mRNA expression. This study could improve the predictive genetic diagnosis of at-risk individuals belonging to families with reduced mRNA expression regardless of presence of mutation.

Project description:BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the APC gene. Recently, biallelic mutations in MUTYH have also been identified in patients with multiple colorectal adenomas and in APC-negative patients with FAP. The aim of this work is therefore to determine the frequency of APC and MUTYH mutations among FAP families from two Spanish populations.MethodsEighty-two unrelated patients with classical or attenuated FAP were screened for APC germline mutations. MUTYH analysis was then conducted in those APC-negative families and in 9 additional patients from a previous study. Direct sequencing, SSCP analysis and TaqMan genotyping were used to identify point and frameshift mutations, meanwhile large rearrangements in the APC gene were screened by multiplex ligation-dependent probe amplification (MLPA).ResultsAPC germline mutations were found in 39% of the patients and, despite the great number of genetic variants described so far in this gene, seven new mutations were identified. The two hotspots at codons 1061 and 1309 of the APC gene accounted for 9,4% of the APC-positive families, although they were underrepresented in Galician samples. The deletion at codon 1061 was not found in 19 APC-positive Galician patients but represented 23% of the Catalonian positive families (p = 0,058). The same trend was observed at codon 1309, even though statistical analysis showed no significance between populations. Twenty-four percent of the APC-negative patients carried biallelic MUTYH germline mutations, and showed an attenuated polyposis phenotype generally without extracolonic manifestations. New genetic variants were found, as well as the two hotspots already reported (p.Tyr165Cys and p.Gly382Asp).ConclusionThe results we present indicate that in Galician patients the frequency of the hotspot at codon 1061 in APC differs significantly from the Catalonian and also other Caucasian populations. Similar results had already been obtained in a previous study and could be due to the genetic isolation of the Galician population. MUTYH analysis is also recommended for all APC-negative families, even if a recessive inheritance is not confirmed.

Dataset Information

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

Purpose

Methods

Results

Conclusion

Publications

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

Similar Datasets

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