The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis

Abstract

Contributors FSA and KSA designed and implemented the study. tM, AKS and SS performed WeS, critical data analyses, interpretation of results and wrote the manuscript. rB performed DNA extraction and analysed the data. SKP, AA and FAD contributed samples and analysed clinical data. FSA and KSA wrote the original draft and critically reviewed the manuscript.

Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel

“…However, we identified 13 frequent variants occurring in five or more subjects, 2 of which are considered likely PVs ( APC c.3920T>A and TP53 c.799C>T), and six of which have been previously classified as PVs ( BRCA1 c.5123C>A, MSH2 c.1964del, MUTYH c.544C>T and c.734G>A, PMS2 c.1376C>G and c.1606C>T). PMS2 c.1376C>G was the most frequent Lynch syndrome-associated variant in a survey of Saudi CRC patients [ 39 ].…”

“…Studies specific to Arab populations have typically screened for tumor-specific rather than broad germline mutations [14,15,26,27], or have focused on one gene or a small number of genes associated with one type of cancer [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. These show that Arab cohorts differ greatly in pathogenic variant prevalence from Western cohorts, and from each other.…”

Updates in the field of hereditary nonpolyposis colorectal cancer

“…At present, no definitive explanation is available for polyp predisposition in biallelic carriers of MMR gene mutations. At least one somatic APC mutation was detected in each of three PMS2-associated polyps examined by Siraj et al [62], implying that inactivation of APC, a gatekeeper of cellular proliferation, is important for tumor development. In MSH3-associated tumors, the observed inflammatory infiltration and the spectrum of somatic APC mutations (small deletions at repeat sequences) pointed to the significance of MMR deficiency in tumorigenesis [57].…”

“…In CMMRD, germline inactivation of both alleles of the MMR gene in question, together with somatic polymerase exonuclease domain mutations, was shown to result in an 'ultra-hypermutated' tumor phenotype (over 100 mutations/Mb) in brain tumors, whereas gastrointestinal polyps revealed no increased mutational load compared with adult polyps [61]. Moreover, no microsatellite instability (at dinucleotide or trinucleotide repeats) was observed in a polyp from a homozygous carrier of a nonsense mutation in PSM2 [62]. Tumor tissues from biallelic MSH3 mutation carriers showed a distinct form of microsatellite instability called EMAST (Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats) [57].…”

Molecular pathology of colorectal cancer

“…15 Despite the importance of the LS diagnosis, only 3 groups have published research on the CRC syndrome in Saudi Arabia. [19][20][21] The frequency of LS based on the 3 published articles from 2 of the 3 groups was between 0.99-7.2%. Siraj et al, 19 who have so far found a LS prevalence of 2.2% )up from 0.99%(, used a combination of MMR immunohistochemistry, microsatellite analysis by PCR, BRAF mutation testing, and deep sequencing to investigate mutations in the MMR genes, and found that 26 of the 1207 CRC cases harboured various germline mutations in MLH1, MSH2, PMS2, MSH6, and EPCAM.…”