Rastreamento de variantes patogênicas germinativas em genes associados à predisposição hereditária ao câncer colorretal

Abstract

Colorectal cancer (CRC) is among the most lethal cancers and ranks as the third most common in both the Brazilian and global populations. Its high prevalence makes it a significant public health concern. Approximately 5% of CRC cases have a hereditary origin and are classified as Hereditary Colorectal Cancer Predisposition Syndromes (HCCPS). Germline Pathogenic Variants (GPVs) in genes such as APC, MUTYH, MLH1, MSH2, MSH6, among others, are associated with these syndromes and may trigger physiological changes that precede CRC. One of the main challenges in clinical management is the phenotypic overlap among different HCCPS. Identifying GPV is essential to improve care for affected individuals and atrisk family members, contributing to primary prevention and early diagnosis strategies. Objective: To describe the genetic aspects of patients at high risk for HCCPS treated at the Professor Alberto Antunes University Hospital of the Federal University of Alagoas (HUPAA/UFAL). Methods: GPV screening in genes associated with HCCPS was performed using Next-Generation Sequencing (NGS). Variant validation was conducted at the Human Molecular Genetics Laboratory (LGMH/HUPAA/UFAL) using the allele-specific polymerase chain reaction (AS-PCR) technique. Genotype-phenotype correlations were established based on public databases and literature review. Results: Fourteen families at high risk for HCCPS were analyzed. In six participants, six GPVs and one Variant of Uncertain Significance (VUS) were identified in the following genes: APC (c.3927_3931delAAAGA; c.847C>T; c.1315_1316dup), MUTYH (c.452A>G; c.1063delC), SMAD4 (c.1139+3A>G), and BRCA1(c.1687C>T). Genotype-phenotype correlation was established in 28.6% of participants. All individuals received post-test genetic counseling, and diagnostic tests using AS-PCR were implemented at LGMH/HUPAA/UFAL and are available for future incorporation into the Brazilian Unified Health System (SUS). Conclusions: These findings support the literature by demonstrating the association between different GPVs and overlapping phenotypes, and they expand knowledge on genotype-phenotype correlations, particularly involving BRCA1 and SMAD4. The study reinforces the importance of GPV screening in HCCPS and highlights its clinical applicability. The investigation of at-risk relatives through pre-test genetic counseling represented a valuable opportunity for primary prevention actions.