Germline mutations in a DNA repair pathway are associated with familial colorectal cancer
Pingping Xu, … , Ying-Xuan Chen, Jing-Yuan Fang
Pingping Xu, … , Ying-Xuan Chen, Jing-Yuan Fang
Published September 22, 2021
Citation Information: JCI Insight. 2021;6(18):e148931. https://doi.org/10.1172/jci.insight.148931.
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Research Article Gastroenterology Genetics

Germline mutations in a DNA repair pathway are associated with familial colorectal cancer

Abstract

Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.

Authors

Pingping Xu, Danfeng Sun, Yaqi Gao, Yi Jiang, Ming Zhong, Gang Zhao, Jinxian Chen, Zheng Wang, Qiang Liu, Jie Hong, Haoyan Chen, Ying-Xuan Chen, Jing-Yuan Fang

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Figure 2

Gene discovery and characterization.

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Gene discovery and characterization. (A) Pedigree K. Squares indicate ma...
(A) Pedigree K. Squares indicate male family members, and circles represent female members. A slash through a symbol indicates that the family member has died. Filled symbols indicate a clinically affected family member. The proband is indicated by an arrow. WES analysis was performed on 2 individuals, which are marked by the letter S. The CHEK2_p.Q27* mutant germline allele that was detected by Sanger sequencing is shown below each individual. “V/N” indicates a heterozygous variant carrier, and “N/N” indicates a noncarrier. Age of tumor diagnosis is shown beneath each symbol. (B) The filter-based computational algorithm that is used to narrow candidate variants for pedigree K. Single-nucleotide variant, SNV; minor allele frequency, MAF. (C) The functional domains of Chk2 and the predicted truncated Chk2 protein that would result from the variant. SQ/TQ indicates the SQ/TQ motif, which is the consensus site for phosphoinositide-kinase–related kinases (PIKKs). FHA indicates the forkhead-associated domain. NLS indicates the nuclear localization signal. (D) Sanger sequencing–based validation of the germline CHEK2_p.Q27* mutation in individuals of this pedigree. The red arrowhead and black box indicate the location of the heterozygous substitution of C to T in the mutated locus of CHEK2.