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.
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Data availability
Raw sequence tags were deposited in the NCBI Short Read Archive (SRA: https://www.ncbi.nlm.nih.gov/Traces/sra), under the accession number SRP199998. RNA-seq data sets were deposited in the NCBI Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/) under the accession number GSE132024.
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Funding
This study was cooperatively supported by the National Research Foundation of Korea (NRF) (2020R1C11009345, 2017R1A2B1009062, and 2016R1E1A1A02919844) grants funded by the Korea government (NSIT).
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This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (registration no.: 2019-1367).
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All samples were collected from the Institutional Bioresource Center, with written consent from patients [registration no. 2015-08(98)].
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432_2020_3391_MOESM1_ESM.xlsx
Fig. A1. Oncoplots of significant gene mutations between the respective item+ and item- groups of 12 items (a. items 1-8 , b. items 9-12). All differential genes of respective items presented p < 0.05, except for items 7 and 10 (p < 0.001) (XLSX 3669 kb)
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Kim, J.C., Kim, J.H., Ha, Y.J. et al. Analysis of genomic pathogenesis according to the revised Bethesda guidelines and additional criteria. J Cancer Res Clin Oncol 147, 117–128 (2021). https://doi.org/10.1007/s00432-020-03391-8
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DOI: https://doi.org/10.1007/s00432-020-03391-8