Abstract 460P
Background
Genetic factors play an important role in colorectal cancer (CRC) risk, and germline mutations in the DNA damage repair (DDR) genes have also been reported to be implicated in CRC heritability. Here, we aimed to determine the prevalence and significance of germline DDR and well-established CRC-risk gene variants in CRCs with paired somatic analyses.
Methods
Next-generation sequencing (NGS) was performed on 2160 Chinese patients with CRC using well-designed cancer gene panel. Germline/somatic variations were identified and assessed for pathogenicity and likely pathogenicity. Patients with pathogenic germline variants were regarded to have a second hit if a somatic deleterious alteration in the same gene was detected.
Results
Of 2160 CRCs, 136 pathogenic germline mutations in 133 patients (133/2160, 6.1%) were identified in 21 genes. These mutations fell predominantly in MLH1 (n=22, 16.2%), MSH2 (n=14, 10.3%), MSH6 (n=11, 8.1%), MUTYH (n=10, 7.4%), APC (n=10, 7.4%), BRCA (9 in BRCA2, and 1 in BRCA1, n=10, 7.4%), ATM (n=8, 5.9%), BLM (n=7, 5.1%), RAD50 (n=7, 5.1%), and CHEK2 (n=7, 5.1%). Early-onset CRCs with age ≤ 50 had a trend of higher germline mutation frequency than average-onset CRC patients (9.6% vs 6.0%, P=0.094), especially in MMR, APC and CHEK2. Patients with pathogenic germline DDR gene mutations were more likely to present higher TMB level (median TMB 11.3 vs 7.26, P < 0.001), MSI-H phenotype (35.8% vs 4.8%, P < 0.001) and an earlier onset age of CRC (median age 54.0 vs 57.0, P=0.016) compared to the non-carriers. Somatic sequencing identified second hits in 24/133 (18%) patients with germline variants. In our cohort, 52 participants carried at least one pathogenic germline variants in MMR genes, and 41 (78.8%) were MSI-H, while 13 participants with a second hit in MMR genes were all MSI-H, including 2 (9.1%) of 22 MLH1 carriers, 1 (7.1%) of 14 MLH2 carriers, 8 (72.7%) of 11 MSH6 carriers, and 2 (40%) of 5 PMS2 carriers, and had significantly higher TMB (median TMB 108 VS 66.9, P =0.004).
Conclusions
Approximately 6.1% of CRC patients carried pathogenic or likely-pathogenic germline variants, and additional somatic second hit increases the instability of genome in CRC, which might result in a better chance to benefit from immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.