Assessment of "gene-environment" interaction in cases of familial and sporadic pancreatic cancer

Our plain-English summary of Assessment of "gene-environment" interaction in cases of familial and sporadic pancreatic cancer, by T.P. Yeo, R.H. Hruban, J. Brody, et al (Journal of Gastrointestinal Surgery, 2009).

The study

• Authors: T.P. Yeo, R.H. Hruban, J. Brody, K. Brune, S. Fitzgerald, C.J. Yeo
• Journal: Journal of Gastrointestinal Surgery
• Published: 2009;13(8):1487-94
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. This study characterizes one of the largest national registries of familial PC (FPC) and sporadic PC (SPC), focusing on demographics, clinical factors, self-reported environmental and occupational lifetime exposures, and survival status.

Background: Reported risk factors for PC include advancing age, a family history of PC, high-risk inherited syndromes, cigarette, cigar, and pipe smoking, exposure to occupational and environmental carcinogens, African-American race, high fat/high cholesterol diet, obesity, chronic pancreatitis, and diabetes mellitus.

Patients And Methods: This retrospective cross-sectional, case-only analysis includes cases of FPC (n = 569) and SPC (n = 689) from the Johns Hopkins National Familial Pancreas Tumor Registry (NFPTR) enrolled between 1994 and 2005.

Results: FPC smokers with environmental tobacco smoke (ETS) exposure were diagnosed at a significantly younger mean age (63.7 years) as compared to FPC non-smokers without ETS exposure (66.6 years; p = 0.05). Non-smoker ETS-exposed cases were diagnosed with PC at a significantly younger mean age (64.0 years) compared to non-smoker non-ETS-exposed cases (66.5 years) (p < 0.0004). The mean age at diagnosis for Ashkenazi Jewish SPC subjects was significantly younger (by 2.1 years) than Ashkenazi Jewish FPC cases (p = 0.05). In addition, Ashkenazi Jewish FPC subjects who smoked were diagnosed 5.9 years earlier than Ashkenazi Jewish FPC non-smokers (p = 0.05). The median length of survival for unresected FPC cases was significantly shorter (168 days) as compared to unresected SPC cases (200 days) (p = 0.04). Survival was improved in resected cases, 713 days for FPC cases and 727 days for SPC cases, but was not significantly different between the groups (p = 0.4). Mild to moderate multiplicative interaction was found between a family history of PC and exposure to asbestos, environmental radon, and environmental tobacco smoke (ETS), as evidenced by odds ratios >1.0.

Conclusions: These are the first data to show that occupational and environmental exposures may act synergistically with inherited or acquired genetic polymorphisms, resulting in earlier occurrence of PC. Exposure to cigarette smoking and ETS exposure in non-smokers when younger than 21 years of age are associated with a younger mean age of diagnosis in FPC and SPC cases and Ashkenazi Jewish smokers, when compared to non-exposed cases. Risk prediction models which take into account environmental exposures as well as family history may more accurately predict the risk of PC. High-risk individuals will likely benefit from early identification of pre-malignant lesions and molecular profiling, as methods of early detection, prevention, and personalized therapy.

In plain English

This study was about pancreatic cancer, not mesothelioma or asbestosis. The authors analyzed questionnaires from a Johns Hopkins registry of 1,258 people with pancreatic cancer enrolled between 1994 and 2005. Of these, 569 were familial cases (two or more first-degree relatives affected) and 689 were sporadic cases. Many questionnaires were filled in by a family member or proxy: 77.9% in the familial group and 50.9% in the sporadic group. There was no cancer-free comparison group, so the two patient groups were compared with each other. Among cases with a known answer, occupational asbestos exposure was reported more often by familial cases (28.0%) than sporadic cases (17.5%). The authors described this as mild interaction between family history and asbestos (odds ratio 1.83, 95% CI 1.31 to 2.56). They reported moderate interaction for residential radon and none for smoking. No asbestos fiber type or amount was reported. Non-smokers exposed to secondhand smoke before age 21 were diagnosed younger than unexposed patients. The authors suggested that asbestos and radon may matter in familial pancreatic cancer. They noted the limits of retrospective, self-reported data.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective, cross-sectional, case-only descriptive analysis of registry questionnaire data, with no cancer-free control group. Familial and sporadic pancreatic cancer cases were compared with each other.
• Who was studied: 1,258 people with pancreatic cancer (infiltrating ductal adenocarcinoma) living in the US, from the Johns Hopkins National Familial Pancreatic Tumor Registry, covering January 1, 1994 to April 15, 2005. The group was 569 familial cases (two or more first-degree relatives with pancreatic cancer) and 689 sporadic cases. It included 673 men and 585 women and was 93.4% Caucasian.
• Exposure: Self-reported lifetime occupational and environmental exposures (more than 20 items) from the registry questionnaire. These included occupational asbestos, with no fiber type, product, or dose given, as well as residential radon, pesticides and herbicides, coal products, welding, radiation and wood dust. Cigarette smoking and environmental tobacco smoke (secondhand smoke, defined as regularly spending more than 1 hour per day in a room where someone else smoked) were also studied. Missing or unknown answers (5% to 30% per item) were excluded from the analysis.
• Main results:
  • Occupational asbestos exposure was reported by 28.0% of familial cases and 17.5% of sporadic cases (p less than 0.004). These percentages were calculated after excluding missing or unknown answers, so they apply to cases with a known answer, not to all 569 and 689 cases.
  • The authors reported 'mild' multiplicative interaction between a family history of pancreatic cancer and occupational asbestos. The odds ratio was 1.83 (95% CI 1.31 to 2.56, p less than 0.002), compared with the sporadic group.
  • The authors reported 'moderate' multiplicative interaction between family history and residential radon. The odds ratio was 2.39 (95% CI 1.39 to 4.30, p less than 0.0008).
  • The authors found no multiplicative interaction between family history and ever smoking (odds ratio 0.86, 95% CI 0.68 to 1.09, p 0.20) or wood dust (odds ratio 1.49, 95% CI 0.86 to 2.61).
  • The authors reported 'mild' interaction for environmental tobacco smoke exposure between 41 and 60 years of age (odds ratio 1.31, 95% CI 1.04 to 1.65, p 0.02).
  • Among non-smokers, those exposed to environmental tobacco smoke before age 21 were diagnosed younger than the unexposed. The difference was 5.7 years earlier in familial cases (mean 59.6 vs 65.3 years) and 9.1 years earlier in sporadic cases (56.7 vs 65.8 years).
  • Regular smokers were diagnosed younger than never-smokers. In familial cases the mean age was 63.4 vs 65.6 years (p 0.02). In sporadic cases it was 62.6 vs 63.9 years (p 0.26, not significant).
  • Among Ashkenazi Jewish familial cases, non-smokers were diagnosed at a mean age of 70.3 years and smokers at 64.4 years (p 0.05).
  • For patients without surgery, median survival was 168 days in familial cases and 200 days in sporadic cases (p 0.04). For patients with surgery, it was 713 days in familial cases and 727 days in sporadic cases, and only the difference without surgery was significant.
  • Questionnaires were completed by a family member or proxy for 77.9% of familial cases and 50.9% of sporadic cases.
• The authors' conclusion: The authors concluded that the more frequent reporting of occupational asbestos and residential radon exposure among familial cases may indicate a biological role for these exposures in the familial form of pancreatic cancer. They saw this as supported by the interaction findings.
• Limitations the authors state:
  • The study was a descriptive, case-only study based on a retrospective database and self-reported data.
  • Obtaining longitudinal, quantitative assessments of exposure to secondhand smoke, asbestos and residential radon was substantially difficult.
  • Incomplete or missing environmental exposure assessment restricts how far the findings can be generalized.

Topics

Medical terms in this study, explained in our Lexicon: Cancer Registry, Odds Ratio, Environmental Exposure, Molecular Profiling.

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• The influence of gene-gene and gene-environment interactions on the risk of asbestosis — A. Franko, V. Dolžan, et al. (2013)
• Genome-wide Gene-Asbestos Exposure Interaction Association Study Identifies a Common Susceptibility Variant on 22q13.31 Associated with Lung Cancer Risk — C.Y. Liu, I. Stücker, et al. (2015)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)

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