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Background <p>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 (<i>MLH1</i>,<i> MSH2</i>,<i> MSH6</i>,<i> PMS2</i>) and other susceptibility genes (<i>APC</i>,<i> EPCAM</i>). In Pakistan, small-range PVs in <i>MLH1</i> and <i>MSH2</i> 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 <i>MLH1</i>,<i> MSH2</i>,<i> MSH6</i>, and the 3′ end of <i>EPCAM</i> remains uncharacterized.</p> Methods <p>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 <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and the 3′ end of <i>EPCAM</i> were analyzed using multiplex ligation-dependent probe amplification (MLPA). Deletion breakpoints were characterized using long-range polymerase chain reaction (PCR) and Sanger sequencing.</p> Results <p>Five distinct <i>MSH2</i> 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 <i>MLH1</i>,<i> MSH6</i>, or the 3′ end of <i>EPCAM</i>. Notably, 87.5% of patients with <i>MSH2</i> LGRs belonged to Punjabi ethnicity.</p> Conclusions <p>Our findings demonstrate that <i>MSH2</i> 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.</p>

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

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  • 发表日期：

    2025年11月19日

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

摘要

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.