Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Cancer Epidemiol. 2021 Jun;72:101941. doi: 10.1016/j.canep.2021.101941. Epub 2021 Apr 28.
Germline predisposition variants associated with colorectal cancer (CRC) have been identified but all are not yet identified. We sought to identify the responsible predisposition germline variant in an extended high-risk CRC pedigree that exhibited evidence of linkage to the 18q12.2 region (TLOD = +2.81).
DNA from two distantly related carriers of the hypothesized predisposition haplotype on 18q12.2 was sequenced to identify candidate variants. The candidate rare variants shared by the related sequenced subjects were screened in 3,094 CRC cases and 5x population-matched controls from UKBiobank to test for association. Further segregation of the variant was tested via Taqman assay in other sampled individuals in the pedigree.
Analysis of whole genome sequence data for the two related hypothesized predisposition haplotype carriers, restricted to the shared haplotype boundaries, identified multiple (n = 6) rare candidate non-coding variants that were tested for association with CRC risk in UKBiobank. A rare intronic variant ofCELF4 gene, rs568643870, was significantly associated with CRC (p = 0.004, OR = 5.0), and segregated with CRC in other members of the linked pedigree.
Evidence of segregation in a high-risk pedigree, case-control association in an external dataset, and identification of additional CRC-affected carriers in the linked pedigree support a role for a rareCELF4 intronic variant in CRC risk.
已鉴定出与结直肠癌（CRC）相关的种系易感性变异体，但并非所有变异体均已鉴定。我们试图在一个表现出与 18q12.2 区域（TLOD = +2.81）连锁证据的扩展高风险 CRC 家系中鉴定负责的种系易感性变异体。
对假设的 18q12.2 易感性单倍型的两个远距离相关携带者的 DNA 进行测序，以鉴定候选变异体。在来自 UKBiobank 的 3094 例 CRC 病例和 5 倍人群匹配对照中筛选相关测序对象共有的候选罕见变异体，以测试其关联。通过 Taqman 测定法在该家系中的其他抽样个体中进一步测试变体的分离。
对两个相关假设的易感性单倍型携带者的全基因组序列数据进行分析，仅限于共享的单倍型边界，鉴定出多个（n = 6）罕见的候选非编码变异体，这些变异体在 UKBiobank 中测试与 CRC 风险的关联。CELF4 基因的罕见内含子变异体 rs568643870 与 CRC 显著相关（p = 0.004，OR = 5.0），并且在连锁家系的其他 CRC 患者中分离。
在高风险家系中存在分离证据，在外部数据集的病例对照关联，以及在连锁家系中鉴定出其他 CRC 受影响的携带者，支持罕见的 CELF4 内含子变异体在 CRC 风险中的作用。
