Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

Jun-Xiao Zhang, Lei Fu, Richarda M de Voer, Marc-Manuel Hahn, Peng Jin, Chen-Xi Lv, Eugène Tp Verwiel, Marjolijn Jl Ligtenberg, Nicoline Hoogerbrugge, Roland P Kuiper, Jian-Qiu Sheng, Ad Geurts van Kessel

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

12 Citaten (Scopus)


AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases.

METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ≤ 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.

RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001).

CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.

Originele taal-2Engels
Pagina's (van-tot)4136-49
Aantal pagina's14
TijdschriftWorld journal of gastroenterology
Nummer van het tijdschrift14
StatusGepubliceerd - 14 apr. 2015
Extern gepubliceerdJa


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