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

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, whileUSP40,HCFC1, andHSPG2mutation rates were higher in rectal than colon cancer.FAT4mutation 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 ofCOL6A5andMGAM2were significantly andSETD5was assumably, associated CRC pedigree with concurrent gastric cancer (GC). The predicted deleterious/damaging germline variants,SH2D4Ars35647122, was associated with synchronous/metachronous CRC with related tumors, whileNUP160rs381660 andKRTAP27-1rs2244485 were potentially associated with a GC pedigree and less strictly defined hereditary CRC, respectively.SH2D4AandNUP160acted 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.

Automated summary

Genomic analysis based on the revised Bethesda guidelines and additional criteria revealed specific somatic alterations related to colorectal cancer subtypes, such as location, early onset, and MSI status. Certain gene mutations were associated with gastric cancer in CRC pedigrees, while further validation is required for surveillance strategies in suspected individuals.