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

• Published in: Genetics in medicine Vol. 17; no. 10; pp. 815 - 821
• Main Authors: Inra, Jennifer A., Steyerberg, Ewout W., Grover, Shilpa, McFarland, Ashley, Syngal, Sapna, Kastrinos, Fay
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2015; Elsevier Limited
• Subjects: 631/208/457; 692/699/1503/1504/1885; 692/700/139/1512; Adenomatous Polyposis Coli - diagnosis; Adenomatous Polyposis Coli - epidemiology; Adenomatous Polyposis Coli - genetics; Alleles; Biomedicine; Cross-Sectional Studies; DNA Glycosylases - genetics; Female; Genetic Testing; Heterozygote; Human Genetics; Humans; Laboratory Medicine; Male; Middle Aged; Mutation; Mutation Rate; original-research-article; Phenotype; Racial Groups - genetics; Tumor Burden; phenotype; associated polyposis; race; familial adenomatous polyposis; genetic testing
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2014.199

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. Genet Med 17 10, 815–821.