Development of a polygenic risk score based on somatic and germline genetic information from patients with colorectal cancer

Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women. Approximately 70% of CRC cases originate from spontaneous point mutations in oncogenes, tumor suppressor genes, and genes related to DNA repair mechanisms (Nigin et al., 2023). The remaining 30% result from hereditary mutations, of which 5-6% involve high-penetrance genes. Genetic predisposition due to pathogenic germline variants in high-risk cancer-associated genes has been implicated in 2-8% of all CRC cases, increasing to 6-10% when considering pathogenic mutations in both high- and moderate-penetrance genes.

For individuals with certain hereditary cancer syndromes, the risk of developing colorectal cancer can reach 50-80% in the absence of endoscopic and/or surgical intervention. Therefore, characterizing high-, moderate-, and low-penetrance genes within a population is crucial for understanding hereditary tumorigenesis and guiding more cost-effective screening strategies.

Genetic studies comparing genomes from populations of different ethnic backgrounds have demonstrated that ancestry plays a significant role in genetic predisposition to CRC. Given the high level of genetic admixture in the Brazilian population, studies focused solely on populations of European ancestry fail to provide a representative model for application in highly admixed populations like Brazil.

In this context, the present study aims to utilize next-generation sequencing (NGS) in a cohort representative of the Brazilian population with CRC and controls to develop a Polygenic Risk Score (PRS). This score could impact cancer screening and prevention strategies, as well as genetic counseling for patients and their families. The hypothesis is that genetic mapping-including ancestry, germline, and tumor genetic variability-in Brazilian colorectal cancer patients will provide valuable data for developing a PRS that may eventually guide more targeted and cost-effective screening strategies for our population.

Inclusion Criteria:

• > 18 years;
• Histologically confirmed diagnosis of colorectal cancer;
• Have available tumor material for somatic sequencing, obtained from biopsy or routine surgery;
• Sign the informed consent form (ICF) for the study.

Exclusion Criteria:

• Pregnants

Of the 500 patients included, approximately 56% will be recruited from participants self-identified as brown, black, or indigenous, with the remaining percentage distributed between white and yellow. Of these individuals, at least 50% will be women, corresponding to the sex and race distribution in the Brazilian population reported in the latest IBGE census in 2022.