Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing

Abstract

Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.

Epidemiology of cancer in Saudi Arabia thru 2010–2019: a systematic review with constrained meta-analysis<span style="font-size: 12px"> Running title: epidemiology of cancer in Saudi Arabia thru 2010–2019</span>

“…Out of the overall seven publications reporting different forms of risk factors ( Table 1 ; Figure 7 ), six studies reported genetic polymorphism as the possible risk factors. The adjusted OR (95%CI) ranged from 1.00 (0.50–2.00) to 1.00 (0.50–2.30) [11] , [49] – [53] . Two studies have attributed family history as a possible risk for CRC, with OR (95%CI) ranged from 1.00 (0.50–2.3) to 2.8 (2.00–4.1) [8] , [11] .…”

“…The adjusted OR (95%CI) ranged from 1.00 (0.50–2.00) to 1.00 (0.50–2.30) [11] , [49] – [53] . Two studies have attributed family history as a possible risk for CRC, with OR (95%CI) ranged from 1.00 (0.50–2.3) to 2.8 (2.00–4.1) [8] , [11] . Only one study has highlighted ulcerative colitis and fatty diet as possible risk factors for CRC with OR (95%CI) of 2.8 (2.0–2.4) [8] .…”

“…In 2018, CRC accounts for 14.6% of total cancers in the country [5] . The risk factors for CRC may be genetic, environmental, age, gender and other inflammatory conditions of the digestive tract [10] , [11] .…”

Genetic Evaluation of Turkish patients with Colorectal Carcinoma in Terms of Lynch Syndrome by Targeted Next Generation Sequencing

“…In our study, we found 3 variants that had large deletion (33%; 3/9). Alqahtani et al (21) carried out molecular analysis of MLH1, MSH2, MSH6 and PMS2 genes by NGS and MLPA in 13 of 33 Saudi patients with CRC <60 years at diagnosis. Nine variants were found (4 in MLH1 and 5 in MSH2) as pathogenic or likely pathogenic in 9 of the 13 patients (69%).…”

Lifetime Attributable Risk Estimates of Secondary Cancer after External Radiotherapy among Colorectal Cancer Survivors in Saudi Arabia

“…Risk factors such as excess weight, sedentary lifestyle, diet rich in processed food, smoking, inflammatory bowel disease were found to contribute to 60-65% of CRC for both genders. Family history, due to the high rate of consanguineous marriage, and genetic syndrome (familial adenomatous polyposis or Lynch syndrome) account for 25-30% and 5%, respectively [27][28][29] . Polymorphisms of the ADIPOQ 30 , XRCC1, RETN 31 , and vitamin D receptor VDR 32 due to low vitamin D intake, have also been associated with increased risk CRC among Saudi older population.…”