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Next-generation sequencing with comprehensive bioinformatics analysis facilitates somatic mosaic APC gene mutation detection in patients with familial adenomatous polyposis

 Borahm Kim  ;  Dongju Won  ;  Mi Jang  ;  Hoguen Kim  ;  Jong Rak Choi  ;  Tae Il Kim  ;  Seung-Tae Lee 
 BMC Medical Genomics, Vol.12(1) : 103, 2019 
Journal Title
 BMC Medical Genomics 
Issue Date
APC ; Colorectal cancer ; Familial adenomatous polyposis ; Next-generation sequencing ; Somatic mosaic mutation
BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal tumor characterized by numerous adenomatous colonic polyps that often lead to colon cancer. Although most patients with FAP harbored germline mutations in APC gene, it was recently recognized that patients with clinical FAP, but without detectable pathogenic mutations, could be associated with somatic mosaic APC mutation. METHODS: We reanalyzed the nest-generation sequencing (NGS) gene panel testing results of patients who were diagnosed with FAP, but did not have APC mutations, at Yonsei Cancer Prevention Center between July 2016 and March 2018. We tested several variant calling algorithms to identify low level mosaic variants. In one patient with a low frequency APC mutation, NGS analysis was performed together with endoscopic biopsy. Variant calling tools HaplotypeCaller, MuTect2, VarScan2, and Pindel were used. We also used 3'-Modified Oligonucleotides (MEMO)-PCR or conventional PCR for confirmation. RESULTS: Among 28 patients with clinical suspicion of FAP but no detectable pathogenic variants of colonic polyposis associated genes, somatic mosaic pathogenic variants were identified in seven patients. The variant allele frequency ranged from 0.3 to 7.7%. These variants were mostly detected through variant caller MuTect2 and Pindel, and were further confirmed using mutant enrichment with MEMO-PCR. CONCLUSIONS: The NGS with an adequate combination of bioinformatics tools is effective to detect low level somatic variants in a single assay. Because mosaic APC mutations are more frequent than previously thought, the presence of mosaic mutations must be considered when analyzing genetic tests of patients with FAP.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Borahm(김보람) ORCID logo https://orcid.org/0000-0003-0923-7744
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Kim, Hogeun(김호근)
Won, Dongju(원동주) ORCID logo https://orcid.org/0000-0002-0084-0216
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Jang, Mi(장미) ORCID logo https://orcid.org/0000-0002-0153-9847
Choi, Jong Rak(최종락) ORCID logo https://orcid.org/0000-0002-0608-2989
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