Circadian Clock Gene Per1 Mutations In Colorectal Cancer (Crc)

12106 Background: PER1 encodes for one of the main negative regulator of the clock genes pathway, which modulates the circadian expression of key target genes at the cellular level. Downregulation of PER1 has been observed in CRC and lower expression levels have been associated with poor survival and increased incidence of liver metastases. Few data are available on PER1 gene mutations (PER1mut) in CRC. Therefore, we aimed to explore the clinical and molecular differences between PER1 mutated versus wild-type (WT) CRCs. Methods: 4079 CRCs tested with tumor profiling (Caris Life Sciences, Phoenix, AZ) were included in this analysis. NextGen sequencing (NGS) was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples using the NextSeq platform (Illumina, Inc., San Diego, CA) on 592 genes. Microsatellite instability high (MSI-H) status was tested by NGS in 3996 tumors. Pathogenicity of PER1mut was estimated using Poly-Phen and SIFT. Results: Main characteristics in the global population were as follow: M/F 52.4/47.6%, median age 61 (16-90 yr), primary tumor right-sided 27.4%/left-sided 43.5%/NOS 29.1%, mutational status all WT 38.7%/RASmut 53.4%/BRAFmut 7.9%, MSI-H 6.6% (n = 262). Overall, 185 unique PER1mut/variants were identified in 304 samples (7.45%); 45 were classified as pathological/possibly pathological (PATHmut) according to predictive scores. PER1mut were significantly associated with right-sided tumor location (p < 0.001) and MSI-H (p < 0.001). Overall incidence of PER1mut and PATHmut in the MSI-H group were 24% and 3.4%, respectively. In the multivariate analyses PATHmut were independently associated with mutations in ARAF, BAP1, CHEK2, NF1, PIK3CA and POLE. Conclusions: Our results provide the first exploratory data on PER1mut association with clinical and molecular features in CRC, in a large population of patients with extensive genetic testing. A deeper understanding of PER1mut pathogenicity and functional role is necessary to guide future analyses. Nevertheless, our results suggest a significant association with MSI-H, possibly reflecting an interplay between mismatch repair status and the clock genes pathway in CRC, consistent with previous data and warranting further investigation.