Analysis of genomic pathogenesis according to the revised Bethesda guidelines and additional criteria

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Title
Analysis of genomic pathogenesis according to the revised Bethesda guidelines and additional criteria
Author(s)
J C Kim; Jong-Hwan Kim; Y J Ha; Chan Wook Kim; K H Tak; Y S Yoon; Y H Kwon; S A Roh; D H Cho; Seon-Kyu KimSeon-Young Kim; Yong Sung Kim
Bibliographic Citation
Journal of Cancer Research and Clinical Oncology, vol. 147, no. 1, pp. 117-128
Publication Year
2021
Abstract
Purpose: As few genotype-phenotype correlations are available for nonsyndromic hereditary colorectal cancer (CRC), we implemented genomic analysis on the basis of the revised Bethesda guideline (RBG) and extended (12 items) to verify possible subtypes. Methods: Patients with sporadic CRC (n = 249) were enrolled, stratified according to the revised Bethesda guidelines (RBG+ and RBG- groups) plus additional criteria. Exome/transcriptome analyses (n = 98) and cell-based functional assays were conducted. Results: We detected 469 somatic and 830 germline gene mutations differing significantly between the positive and negative groups, associated with 12 RBG items/additional criteria. Twenty-one genes had significantly higher mutation rates in left, relative to right, colon cancer, while USP40, HCFC1, and HSPG2 mutation rates were higher in rectal than colon cancer. FAT4 mutation rates were lower in early-onset CRC, in contrast to increased rates in microsatellite instability (MSI)-positive tumors, potentially defining an early-onset microsatellite-stable subtype. The mutation rates of COL6A5 and MGAM2 were significantly and SETD5 was assumably, associated CRC pedigree with concurrent gastric cancer (GC). The predicted deleterious/damaging germline variants, SH2D4A rs35647122, was associated with synchronous/metachronous CRC with related tumors, while NUP160 rs381660 and KRTAP27-1 rs2244485 were potentially associated with a GC pedigree and less strictly defined hereditary CRC, respectively. SH2D4A and NUP160 acted as oncogenic facilitators. Conclusion: Our limited genomic analysis for RBG and additional items suggested that specific somatic alterations in the respective items may enlighten relevant pathogenesis along with the knowledge of germline mutations. Further validation is needed to indicate appropriate surveillance in suspected individuals.
Keyword
Hereditary colorectal cancerRevised Bethesda guidelineNonsyndromicNGSSNP
ISSN
0171-5216
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00432-020-03391-8
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Korea Bioinformation Center > 1. Journal Articles
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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