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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis
Wellington dos Santos, Ariane S Pereira, Thais Laureano, Edilene S de Andrade, Monise T Reis, Felipe AO Garcia, Natalia Campacci, Matias E Melendez, Rui M Reis, Henrique de CR Galvão, Edenir I Palmero
Wellington dos Santos, Ariane S Pereira, Thais Laureano, Edilene S de Andrade, Felipe AO Garcia, Natalia Campacci, Matias E Melendez, Rui M Reis, Edenir I Palmero, Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil
Ariane S Pereira, Edenir I Palmero, Department of Genetics, Brazilian National Cancer Institute - INCA, Rio de Janeiro 20231-050, Brazil
Monise T Reis, Department of Pathology, Barretos Cancer Hospital, Barretos 14784-400, Brazil
Matias E Melendez, Cell and Gene Therapy Program, Brazilian National Cancer Institute - INCA, Rio de Janeiro 20231-050, Brazil
Rui M Reis, Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga 4710-057, Portugal
Rui M Reis, ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
Henrique de CR Galvão, Department of Oncogenetics, Barretos Cancer Hospital, Barretos 14784-400, Brazil
Co-first authors: Wellington dos Santos and Ariane S Pereira.
Author contributions: dos Santos W main investigation; dos Santos W and Pereira AS contributed equally to this article, they are the co-first authors of this manuscript; dos Santos W and Pereira AS wrote original draft, performed formal analysis, and validations; dos Santos W, Pereira AS, Galvão HDCR, Palmero EI, Melendez ME, and Reis RM edited the original draft; Laureano T, de Andrade ES, and Garcia FAO developed the pipeline for quality control, variants calling and in silico analysis and performed them; Campacci N was responsible for patient selection and consent; Reis MT was responsible for cases classification; dos Santos W, Pereira AS, Campacci N, and Reis MT performed the data curation; Galvão HDCR was responsible for patient and families care; Melendez ME, Reis RM, and Galvão HDCR conceptualized the project; Palmero EI supervised, conceptualized and administrated the project; Melendez ME, Reis RM, Galvão HDCR, and Palmero EI reviewed original draft; Melendez ME, Reis RM, Palmero EI, and Galvão HDCR acquired funding; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the National Oncology Care Support Program, No. 25000.056766/2015-64.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Barretos Cancer Hospital, approval No. 56164716.9.0000.5437.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Sequence data has been deposited at the European Genome-phenome Archive, which is hosted by the EBI and the CRG, under accession number EGAD50000000842.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Edenir I Palmero, PhD, Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Viléla, 1331, Barretos 14784-400, Brazil.
edenirip@yahoo.com.br
Received: January 16, 2025
Revised: February 26, 2025
Accepted: July 1, 2025
Published online: August 7, 2025
Processing time: 201 Days and 15.4 Hours
BACKGROUND
Adenomatous polyposis confers an increased risk of developing colorectal cancer. APC and MUTYH are the major genes investigated in patients suspected of having polyposis. In addition to APC and MUTYH genes, other genes, such as POLE, POLD1, NTHL1, MBD4, MSH3 and MLH3, have recently been associated with polyposis phenotypes, conferring heterogeneity in terms of the clinical, etiological and heritable aspects of patients with polyposis.
AIM
To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the APC and MUTYH genes using whole-exome sequencing.
METHODS
Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing. In addition, their clinical-pathological, personal, and family history data were collected.
RESULTS
The mean age at diagnosis was 51 years, and most participants had attenuated forms of polyposis (88.9%), with 63.0% diagnosed with a primary tumor, mostly colorectal cancer (76.5%). Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 participants), including variants in genes involved in the Wnt/β-catenin signaling pathway, such as ST7 L, A1CF, and DKK4, and variants in DNA-repair genes, such as NTHL1, PNKP, and PMS2, as well as a variant found at the FRK gene identified in a patient with classic polyposis at age 19 and with a family history of polyps.
CONCLUSION
This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the APC and MUTYH genes. These findings support the use of next-generation sequencing for screening, expanding the scope of polyposis-related variants beyond these two genes.
Core Tip: Adenomatous polyposis confers an increased risk of developing colorectal cancer, with the APC and MUTYH genes being the major genes involved in these cases. Other genes have been recently associated with polyposis phenotypes, conferring a heterogeneous clinical, etiological, and heritable aspects of patients with polyposis. Here, by whole exome sequencing, we investigated genes potentially related to polyposis in patients without variants in APC and MUTYH genes. The study identified 16 novel genes potentially associated with polyposis, supporting the screening by next-generation sequencing, and expanding beyond the scope of these two genes.
