Homologous recombination deficiency is linked to shorter survival expectancy in late-stage colorectal cancer.

Abstract

e15576 Background: Colorectal cancer patients with high-level microsatellite instability (MSI-H) benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers to predict their prognosis. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients’ overall survival. Methods: We used whole-exome sequencing (WES) to analyze 99 colorectal cancer samples. The patients were further classified into different groups based on their microsatellite status (MS), homologous recombination deficiency (HRD) score, as well as other clinical characteristics, which might associate with clinical outcomes. Afterward, survival analysis and stratification analysis were performed to explore the significant prognosis and predictive indicators in each group. Additionally, we assessed somatic genomic lesions, copy number aberrations, and mutational pathway, and analyzed the differential genetic patterns in distinct clinical benefit groups. Results: The multivariate Cox regression analysis proved that HRD score was associated with significant OS (HR 0.19, 95% CI 0.12-0.94, p = 0.002), suggesting HRD are prognostic factors for late stage CRC. Therefore, the patients were classified into two subgroups according to the value of the HRD scores (HRD-high vs HRD-low). For comparison, the prominent difference was observed in the somatic mutations and copy number alterations (SCNAs). Our results showed TP53 (78%) , APC (50%) and KRAS (41%) as the most frequently cancer-related mutations in CRC, consistent with previous studies. In patients with MSS group, the SMAD4 mutation was occurred frequently (p < 0.01), as well as a distinctive pattern of chromosomal amplification in HRD-high group patients. However, in patients with MSI group, none significant mutations were observed in HRD-high and HRD-low groups. Conclusions: We integrated HRD statue as prognosis and predictive factors for late stage CRC as determined using WES sequencing. Moreover, we also provide a comprehensive differential genetic pattern in stratification of CRC patients, as well as underscore an importance of combining strategy for molecular diagnosis of CRC.