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A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer

  1. Author:
    Jermusyk, Ashley
    Zhong, Jun
    Connelly, Katelyn E.
    Gordon, Naomi
    Perera, Sumeth
    Abdolalizadeh, Ehssan
    Zhang, Tongwu
    O'Brien, Aidan
    Hoskins, Jason W.
    Collins, Irene
    Eiser, Daina
    Yuan, Chen
    Risch, Harvey A.
    Jacobs, Eric J.
    Li, Donghui
    Du, Mengmeng
    Stolzenberg-Solomon, Rachael Z.
    Klein, Alison P.
    Smith, Jill P.
    Wolpin, Brian M.
    Chanock, Stephen J.
    Shi, Jianxin
    Petersen, Gloria M.
    Westlake,Christopher
    Amundadottir, Laufey T.

  2. Author Address

    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.NCI, Lab Cell & Dev Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA.NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA.Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30303 USA.Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA.Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA.Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21231 USA.Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21287 USA.Georgetown Univ, Dept Med, Washington, DC 20057 USA.Mayo Clin, Dept Quantitat Hlth Sci, Coll Med, Rochester, MN 55905 USA.
    1. Year: 2021
    2. Date: Oct 7
    3. Epub Date: 2021 Sep 23
  2. Journal: American Journal of Human Genetics
  3. Cell Press
    1. 108
    2. 10
    3. Pages: 1852-1865
  5. Type of Article: Article
  6. ISSN: 0002-9297
  1. Abstract:

    Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 x 10(-17), OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p(GTEx) = 1.40 x 10(-69), beta(GTEx) =1 . 99; P-LTG = 1,02 x 10(-30), beta(LTG) = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 x 10(-16), OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.

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  2. DOI: 10.1016/j.ajhg.2021.09.002
  3. PMID: 34559995
  4. PMCID: PMC8546220
  5. View record in Web of Science®
  6. WOS: 000705304300005

Library Notes

  1. Fiscal Year: FY2021-2022
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