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Evidence for a major gene influencing risk of pancreatic cancer.

Abstract

Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer.

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  • Authors+Show Affiliations

    ,

    Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    , , , ,

    Source

    Genetic epidemiology 23:2 2002 Aug pg 133-49

    MeSH

    Adenocarcinoma
    Age of Onset
    Aged
    Aged, 80 and over
    Chi-Square Distribution
    Female
    Genes, Dominant
    Genetic Predisposition to Disease
    Humans
    Likelihood Functions
    Male
    Middle Aged
    Neoplastic Syndromes, Hereditary
    Pancreatic Neoplasms
    Registries
    Retrospective Studies
    Risk Factors
    Smoking
    United States

    Pub Type(s)

    Journal Article
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12214307

    Citation

    Klein, Alison P., et al. "Evidence for a Major Gene Influencing Risk of Pancreatic Cancer." Genetic Epidemiology, vol. 23, no. 2, 2002, pp. 133-49.
    Klein AP, Beaty TH, Bailey-Wilson JE, et al. Evidence for a major gene influencing risk of pancreatic cancer. Genet Epidemiol. 2002;23(2):133-49.
    Klein, A. P., Beaty, T. H., Bailey-Wilson, J. E., Brune, K. A., Hruban, R. H., & Petersen, G. M. (2002). Evidence for a major gene influencing risk of pancreatic cancer. Genetic Epidemiology, 23(2), pp. 133-49.
    Klein AP, et al. Evidence for a Major Gene Influencing Risk of Pancreatic Cancer. Genet Epidemiol. 2002;23(2):133-49. PubMed PMID: 12214307.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Evidence for a major gene influencing risk of pancreatic cancer. AU - Klein,Alison P, AU - Beaty,Terri H, AU - Bailey-Wilson,Joan E, AU - Brune,Kieran A, AU - Hruban,Ralph H, AU - Petersen,Gloria M, PY - 2002/9/6/pubmed PY - 2002/11/26/medline PY - 2002/9/6/entrez SP - 133 EP - 49 JF - Genetic epidemiology JO - Genet. Epidemiol. VL - 23 IS - 2 N2 - Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer. SN - 0741-0395 UR - https://www.unboundmedicine.com/medline/citation/12214307/Evidence_for_a_major_gene_influencing_risk_of_pancreatic_cancer_ L2 - https://doi.org/10.1002/gepi.1102 DB - PRIME DP - Unbound Medicine ER -