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

<b>Background</b>: 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. <b>Methods</b>: 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. <b>Results</b>: Rare inactivating variants (RIVs) in <i>APC</i> had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, <i>p</i> = 5.13 × 10^-12), whereas RIVs in <i>RIMS1</i>, an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, <i>p</i> = 2.03 × 10^-8). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold (<i>p</i> < 2.5 × 10^-6). Based on the sequence kernel association test, nonsynonymous variants in six genes (<i>TNXB</i>, <i>TAP2</i>, <i>GPSM3</i>, <i>ADGRG4</i>, <i>TMEM229A</i>, and <i>ANKRD33B</i>) had a significant association with high-risk CRC. RIVs in <i>APC</i>-the most common high-penetrance genetic factor-were associated with patients with high-risk CRC in the Middle East. Individuals who inherited <i>APC</i> RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. <b>Conclusions</b>: 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.