Whole Exome-Wide Association Identifies Rare Variants in APC Associated with High-Risk Colorectal Cancer in the Middle East.

Background : Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enriched in high-impact rare alleles, which might play a crucial role in the etiology and susceptibility of CRC. Methods : In this study, an exome-wide association analysis was performed in 146 patients with high-risk CRC in the Middle East and 1395 healthy controls. The aim was to identify rare germline variants in coding regions and their splicing sites associated with high-risk CRC in the Middle Eastern population. Results : Rare inactivating variants (RIVs) in APC had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, p = 5.13 × 10 ^-12 ), whereas RIVs in RIMS1 , an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, p = 2.03 × 10 ^-8 ). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold ( p < 2.5 × 10 ^-6 ). Based on the sequence kernel association test, nonsynonymous variants in six genes ( TNXB , TAP2 , GPSM3 , ADGRG4 , TMEM229A , and ANKRD33B ) had a significant association with high-risk CRC. RIVs in APC -the most common high-penetrance genetic factor-were associated with patients with high-risk CRC in the Middle East. Individuals who inherited APC RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. Conclusions : We identified new potential CRC predisposition variants in other genes that could play a role in CRC inheritance. However, large collaborative studies are needed to confirm the association of these variants with high-risk CRC. These results provide information for counseling patients with high-risk CRC and their families in our population.