Work

Contribution of MLH1, MSH2, and MSH6 large genomic rearrangements to Pakistani colorectal cancer patients

Year: 2025

Type: article

Abstract: BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer in Pakistan and poses significant public health challenges. While the majority of CRC cases are sporadic, ~ 5-10% are hereditary, linked to germline pathogenic variants (PVs) in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and other susceptibility genes (APC, EPCAM). In Pakistan, small-range PVs in MLH1 and MSH2 account for 34.5% of hereditary nonpolyposis colorectal cancer (HNPCC)/suspected-HNPCC and 1.1% of non-HNPCC cases. However, the contribution of large genomic rearrangements (LGRs) in MLH1, MSH2, MSH6, and the 3' end of EPCAM remains uncharacterized. METHODS: We comprehensively screened 199 Pakistani CRC patients (HNPCC/suspected-HNPCC:18 and non-HNPCC:181), previously tested negative for small-range PVs in MMR genes. LGRs in MLH1, MSH2, MSH6, and the 3' end of EPCAM were analyzed using multiplex ligation-dependent probe amplification (MLPA). Deletion breakpoints were characterized using long-range polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: Five distinct MSH2 deletions (5' upstream, exons 1-3, exons 1-6, exon 7, and exon 11) were identified in 11.1% (2/18) of HNPCC/suspected-HNPCC and 3.3% (6/181) of non-HNPCC cases. A recurrent 5' upstream deletion was identified in four unrelated patients, including one suspected-HNPCC and three non-HNPCC cases. Other deletions were identified in patients with variable family histories of cancer. No LGRs were detected in MLH1, MSH6, or the 3' end of EPCAM. Notably, 87.5% of patients with MSH2 LGRs belonged to Punjabi ethnicity. CONCLUSIONS: Our findings demonstrate that MSH2 LGRs occur at a notable frequency among Pakistani CRC patients, with a recurrent 5' upstream deletion representing a potential Punjabi founder variant. Inclusion of this deletion into targeted genetic testing panels may enhance diagnostic yield and improve risk stratification for CRC in Pakistan.

Source: Hereditary Cancer in Clinical Practice

DOI: 10.1186/s13053-025-00327-6

Authors: Humaira Naeemi, Noor Muhammad, Asif Loya, Muhammed Aasim Yusuf, Muhammad Usman Rashid

Institution: Shaukat Khanum Memorial Cancer Hospital and Research Center

Language: English

Topic: Genetic factors in colorectal cancer

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,690