Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 23:17:29.
doi: 10.1186/s13053-019-0128-2. eCollection 2019.

Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

Muhammad Usman Rashid  1 , Humaira Naeemi  1 , Noor Muhammad  1 , Asif Loya  2 , Jan Lubiński  3 , Anna Jakubowska  3   4 , Muhammed Aasim Yusuf  5
Affiliations

Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

Muhammad Usman Rashid et al. Hered Cancer Clin Pract. .

Abstract

Background: Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients.

Methods: Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2.

Results: Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected.

Conclusion: Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

Keywords: HNPCC; Likely pathogenic variants; MMR genes; Pakistan; Pathogenic variants; Suspected-HNPCC.

PubMed Disclaimer

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pedigrees of HNPCC (a-d and f), suspected-HNPCC (e and g-i) and non-HNPCC (j, k) families with pathogenic/likely pathogenic MLH1 or MSH2 variants. a-k: Include families C203, H707, C202, C162, C92, C143, H1075, C49, C85, C122, and C164, respectively. Circles are females, squares are males, and a diagonal slash indicates a deceased individual. Symbols with filled left upper quadrant: unilateral breast cancer. Symbols with filled right lower quadrant: cancer other than breast, the name of that cancer is mentioned. Identification numbers of individuals are below the symbols. The index patient is indicated by an arrow. A, age; BC, breast cancer; CRC, colorectal cancer; D, death. The numbers following these abbreviations indicate age at enrollment, cancer diagnosis or death. M+, positive for pathogenic/likely pathogenic variant
See this image and copyright information in PMC

References

    1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN. 2012. - PubMed
    1. Dominguez-Valentin M, Therkildsen C, Da Silva S, Nilbert M. Familial colorectal cancer type X: genetic profiles and phenotypic features. Mod Pathol. 2015;28:30–36. doi: 10.1038/modpathol.2014.49. - DOI - PubMed
    1. Espenschied CR, LaDuca H, Li S, McFarland R, Gau C-L, Hampel H. Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol. 2017;35:2568–2575. doi: 10.1200/JCO.2016.71.9260. - DOI - PMC - PubMed
    1. Kurzawski G, Safranow K, Suchy J, Chlubek D, Scott RJ, Lubiński J. Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography. J Biochem Biophys Methods. 2002;51:89–100. doi: 10.1016/S0165-022X(02)00003-9. - DOI - PubMed
    1. da Silva FC, de Oliveira Ferreira JR, Torrezan GT, Figueiredo MCP, Santos ÉMM, Nakagawa WT, et al. Clinical and molecular characterization of Brazilian patients suspected to have Lynch syndrome. PLoS One. 2015;10:e0139753. doi: 10.1371/journal.pone.0139753. - DOI - PMC - PubMed

LinkOut - more resources