{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:30:56Z","timestamp":1791405056845,"version":"4.3.3"},"reference-count":30,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)\/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs\/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients.<\/jats:p>","DOI":"10.3390\/ijms232012299","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:29:46Z","timestamp":1665973786000},"page":"12299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-1049","authenticated-orcid":false,"given":"Rong","family":"Bu","sequence":"first","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul K.","family":"Siraj","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep Kumar","family":"Parvathareddy","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5634-5030","authenticated-orcid":false,"given":"Kaleem","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi 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Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Diaz","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija","family":"Alobaisi","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmanaban","family":"Annaiyappanaidu","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Siraj","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamed","family":"AlHusaini","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4715-9396","authenticated-orcid":false,"given":"Osama","family":"Alomar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics-Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail A.","family":"Al-Badawi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics-Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fouad","family":"Al-Dayel","sequence":"additional","affiliation":[{"name":"Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-3419","authenticated-orcid":false,"given":"Khawla S.","family":"Al-Kuraya","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi 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Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/jnci\/djx214","article-title":"International patterns and trends in endometrial cancer incidence, 1978\u20132013","volume":"110","author":"Ferlay","year":"2018","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_3","first-page":"411","article-title":"the Cancer and Steroid Hormone Study Group A population-based study of endometrial cancer and familial risk in younger women","volume":"5","author":"Gruber","year":"1996","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.1200\/JCO.2015.63.9518","article-title":"Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers from GOG210: An NRG Oncology and Gynecologic Oncology Group Study","volume":"33","author":"Goodfellow","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ygyno.2017.06.002","article-title":"Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper","volume":"146","author":"Randall","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1038\/s41436-019-0536-8","article-title":"The proportion of endometrial cancers associated with Lynch syndrome: A systematic review of the literature and meta-analysis","volume":"21","author":"Ryan","year":"2019","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/annonc\/mdw542","article-title":"Practical guidance for mismatch repair-deficiency testing in endometrial cancer","volume":"28","author":"Stelloo","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ygyno.2017.08.016","article-title":"Clinical characteristics of Lynch-like cases collaterally classified by Lynch syndrome identification strategy using universal screening in endometrial cancer","volume":"147","author":"Takahashi","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1148\/rg.2018170075","article-title":"Lynch Syndrome: Genomics Update and Imaging Review","volume":"38","author":"Cox","year":"2018","journal-title":"Radiographics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1111\/1471-0528.16432","article-title":"A mismatch in care: Results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome","volume":"128","author":"Ryan","year":"2021","journal-title":"BJOG"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e140698","DOI":"10.1172\/jci.insight.140698","article-title":"Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome","volume":"5","author":"Golubicki","year":"2020","journal-title":"JCI Insight"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ygyno.2020.10.012","article-title":"Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients","volume":"160","author":"Hampel","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ygyno.2020.07.013","article-title":"Lynch syndrome identification in a Brazilian cohort of endometrial cancer screened by a universal approach","volume":"159","author":"Rosa","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1146\/annurev-genom-083118-015406","article-title":"Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology","volume":"20","author":"Cohen","year":"2019","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9253","DOI":"10.3748\/wjg.v21.i31.9253","article-title":"Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer","volume":"21","author":"Carethers","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1002\/ijc.29948","article-title":"Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes","volume":"138","author":"Villacis","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/path.2215","article-title":"Genome-wide expression analysis of Middle Eastern papillary thyroid cancer reveals c-MET as a novel target for cancer therapy","volume":"213","author":"Siraj","year":"2007","journal-title":"J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1210\/jc.2007-1717","article-title":"Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population","volume":"93","author":"Abubaker","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E215","DOI":"10.1210\/jc.2010-0790","article-title":"Demethylation of TMS1 gene sensitizes thyroid cancer cells to TRAIL-induced apoptosis","volume":"96","author":"Siraj","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Berg, M., Hagland, H.R., and S\u00f8reide, K. (2014). Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe-and gene-specific scoring alternatives on recommended multi-gene panels. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086657"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1136\/gut.2008.155473","article-title":"CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer","volume":"58","author":"Ogino","year":"2009","journal-title":"Gut"},{"key":"ref_22","first-page":"3410","article-title":"Epigenetic patterns in the progression of esophageal adenocarcinoma","volume":"61","author":"Eads","year":"2001","journal-title":"Cancer Res."},{"key":"ref_23","first-page":"5021","article-title":"Fields of aberrant CpG island hypermethylation in Barrett\u2019s esophagus and associated adenocarcinoma","volume":"60","author":"Eads","year":"2000","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1007\/s00439-017-1845-0","article-title":"Expanding the spectrum of germline variants in cancer","volume":"136","author":"Siraj","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1038\/s41467-018-06159-4","article-title":"Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects","volume":"9","author":"Regier","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gillis, S., and Roth, A. (2020). PyClone-VI: Scalable inference of clonal population structures using whole genome data. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-03919-2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"i333","DOI":"10.1093\/bioinformatics\/bts378","article-title":"DELLY: Structural variant discovery by integrated paired-end and split-read analysis","volume":"28","author":"Rausch","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/ijc.30143","article-title":"Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis","volume":"139","author":"Bu","year":"2016","journal-title":"Int. J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12299\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:54:13Z","timestamp":1760144053000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12299"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":30,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012299"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012299","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]}}}