Hereditary factors play a major role in the development of colorectal cancer (CRC), Identification of germline predisposition can have implications on treatment and cancer prevention, Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. This study aimed to determine phenotype and novel germline variants or novel rare pathogenic variants of patients with colon polyposis in Iran.

We recruited 38 participants who has colon polyps more than 20 in clinic-based settingin three major university hospitals in Mashhad, Tehran, Isfahan were eligible for the study then sequenced Blood DNA. Whole Exome Sequencing data was performed in FastQC, Burrows–Wheeler Aligner (BWA-MEM algorithm), GATK Best Practices were used for SNV. Finally, for variant annotation, we used the ANNOVAR tool. We searched for novel germ-line mutations, SNIP and deletion in genes. We used the Gene ontology to further analyze the results of genes obtained from (WES of CRC patient). 22 gene candidate in polyposis. Networks of GO terms and pathways illustrated by, ClueGo (2.5.8), a Cytoscape application (version 3.9.1) ClueGO was used to recognize the main cellular compound (CC), molecular function (MF) and biological process (BP).

In this cohort 38 patient with a mean age of 45.8 (range, 21-74 years) with a majority of men (60.5% (n = 23) and 63.2% (n = 24) were diagnosed ≤ 50. Patient with more than 100 adenomas have 52.6% (n = 20). Personal history of CRC was reported in 31.6% (n = 12) of patients. The highest location of the tumor in the rectum was 33.3% (n = 4). family history of one or more CRC in a first-degree relative was reported in 42.11%(n=16) of participants.. Twenty-six participant carried 1 or more pathogenic mutation including (n=23) with high penetrance mutation and 2 proband with moderate penetrance. The majority of mutation were Frameshift (42.1%) and nine germ line VUS were detected among 38 patients. Two precipitant carried VUS mutation APC genes that one of them had colon polyposis over 100 and another one had 20 colon polyps however both of them had family history of CRC in first-degree relative. Three participants with colon polyposis over 100 had VUS mutation in MLH3, BRCA1/BRCA2, FGFR4 mutation. This evidence suggests possible pathogenicity to this variant. The PPI network for high risk polyposis patient included 21 nodes and 49 edges and MLH1, MSH6, POLE, BRCA1/2, MLH3, MSH3, MUTYH, BLM have dens and strong connection and high score (p-value< 1.0e-16)

CONCLUSIONS: this study demonstrate novel germline mutation in colon polyposis, whole exome sequencing or panel genetic helps identifying a variety of novel genes in patients with colon polyposis syndrome. larger and more robust studies are needed to discover the genetics behind the initial development of colon polyps and CRC, and provide additional insight.