Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with pancreatic cancer.

Abstract

e16252 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 669 Chinese patients with pancreatic cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 495 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 10.46% (70/669) patients exhibited somatic HRR (sHRR) gene mutations. ATM (4%) was the most common mutant gene, followed by BRCA2 (3%), BARD1 (1%), BRCA1 (1%), BRIP1 (1%), RAD51D (1%), CHEK2(1%). The germline HRR (gHRR) gene mutations were identified in 55.67% (118/245) patients. BRCA2 (23%) was the most common mutant gene, followed by ATM (10%), BRCA1 (9%), BRIP1 (9%), PALB2 (8%), BARD1 (7%), FANCL (3%). 1.49% (10/669) patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (3.97 vs 2.13, p<0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (2.13 vs 2.13, p=0.49). In the TCGA cohort, 9.09% (45/495) patients exhibited sHRR gene mutations. The most common mutant gene was ATM (4%), followed by CDK12 (2%) BRCA2 (2%), BARD1 (1%). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (1.03 vs 0.71, p<0.001). Totally, the somatic mutant frequency of HRR genes was similar between Chinese cohort and TCGA cohort (10.46% vs 9.09%, p = 0.113). For the TCGA cohort, the patients with sHRR-Mut had a similar median progression free survival compared to the ones with sHRR-WT (74.4 months vs not reached, p = 0.299). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese pancreatic cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. Our data suggest that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.