Screening for Lynch Syndrome in Young Colorectal Cancer Patients from Saudi Arabia Using Microsatellite Instability as the Initial Test.

Sarah Alqahtani,Fabienne Grieu,Abdulmalik Alsheikh,Rabab Alattas,Benhur Amanuel,Amerigo Carrello,Barry Iacopetta,Miral Mashour,Masood Alqahtani,Khalid Al-Saleh

doi:10.7314/apjcp.2016.17.4.1917

Abstract

Lynch Syndrome (LS) is a familial cancer condition caused by germline mutations in DNA mismatch repair genes. Individuals with LS have a greatly increased risk of developing colorectal cancer (CRC) and it is therefore important to identify mutation carriers so they can undergo regular surveillance. Tumor DNA from LS patients characteristically shows microsatellite instability (MSI). Our aim here was to screen young CRC patients for MSI as a first step in the identification of unrecognized cases of LS in the Saudi population. Archival tumor tissue was obtained from 284 CRC patients treated at 4 institutes in Dammam and Riyadh between 2006 and 2015 and aged less than 60 years at diagnosis. MSI screening was performed using the BAT-26 microsatellite marker and positive cases confirmed using the pentaplex MSI analysis system. Positive cases were screened for BRAF mutations to exclude sporadic CRC and were evaluated for loss of expression of 4 DNA mismatch repair proteins using immunohistochemistry. MSI was found in 33/284 (11.6%) cases, of which only one showed a BRAF mutation. Saudi MSI cases showed similar instability in the BAT-26 and BAT-25 markers to Australian MSI cases, but significantly lower frequencies of instability in 3 other microsatellite markers. MSI screening of young Saudi CRC patients reveals that approximately 1 in 9 are candidates for LS. Patients with MSI are strongly recommended to undergo genetic counselling and germline mutation testing for LS. Other affected family members can then be identified and offered regular surveillance for early detection of LS-associated cancers.

Highlights

Hereditary nonpolyposis colorectal cancer (HNPCC), more commonly known as Lynch syndrome (LS), is an autosomal dominant genetic condition associated with a high risk of colorectal cancer (CRC) (Lynch et al, 2003)
We previously reported the results of microsatellite instability (MSI) testing in young CRC patients as a first screen to detect Lynch Syndrome (LS) in the state of Western Australia (WA) (Schofield et al, 2009)
The incidence of consanguinity in Saudi Arabia (SA) is over 50% (El-Hazmi et al, 1995), it is unclear whether this contributes to a higher incidence of familial cancer syndromes

Summary

Introduction

Hereditary nonpolyposis colorectal cancer (HNPCC), more commonly known as Lynch syndrome (LS), is an autosomal dominant genetic condition associated with a high risk of colorectal cancer (CRC) (Lynch et al, 2003). The incidence of MMR gene mutation carriers is about 1 in 500 in Western populations Identification of these individuals is crucial because it allows them to undergo early and regular surveillance for cancer. It allows their extended family to be screened for additional mutation carriers. CRC patients who were suspected of being at risk for LS were identified through the use of clinical criteria which rely on obtaining a detailed family history of cancer, as outlined in the Amsterdam and Bethesda guidelines (Umar et al, 2004) These guidelines have been associated with low sensitivity for the detection of LS and their implementation in routine clinical practice has been poor (Lynch et al, 2004). Other affected family members can be identified and offered regular surveillance for early detection of LS-associated cancers

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