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) inAPChad 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 inRIMS1, 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, andANKRD33B) had a significant association with high-risk CRC. RIVs inAPC—the most common high-penetrance genetic factor—were associated with patients with high-risk CRC in the Middle East. Individuals who inheritedAPCRIVs 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.
背景：结直肠癌（CRC）呈现出复杂的遗传模式。据推测，CRC中大部分缺失的遗传力可能富集于具有高影响力的罕见等位基因中，这些等位基因可能在CRC的病因和易感性中起关键作用。 方法：本研究对中东地区146例高危CRC患者和1395例健康对照进行了全外显子组关联分析，旨在识别与中东人群高危CRC相关的编码区及其剪接位点的罕见种系变异。 结果：APC基因的罕见失活变异（RIVs）与高危CRC的关联性最强（病例组6/146 vs. 对照组1/1395，OR = 59.7，p = 5.13 × 10⁻¹²），而RAS超家族成员RIMS1基因的RIVs也与高危CRC显著相关（病例组5/146 vs. 对照组2/1395，OR = 24.7，p = 2.03 × 10⁻⁸）。在全外显子组显著性阈值下（p < 2.5 × 10⁻⁶），共发现17个基因的罕见有害变异与高危CRC相关。基于序列核关联检验，六个基因（TNXB、TAP2、GPSM3、ADGRG4、TMEM229A和ANKRD33B）的非同义变异与高危CRC存在显著关联。APC基因的RIVs——作为最常见的高外显率遗传因素——与中东地区高危CRC患者相关。遗传了APC RIVs的个体罹患CRC的风险增加了约60倍，且发病年龄可能更早。 结论：我们在其他基因中识别出可能参与CRC遗传的新潜在易感变异。然而，需要大规模协作研究来确认这些变异与高危CRC的关联。这些结果为我国人群中高危CRC患者及其家庭的遗传咨询提供了信息。
肿瘤(癌症)患者之家