Thorax. 2015 Nov;70(11):1033-9. doi: 10.1136/thoraxjnl-2014-206584.

Evidence for a Genetic Contribution to Non-Smoking-Related Lung Cancer

 

Shamus R Carr1, Wallace Akerley2, Mia Hashibe3, Lisa A. Cannon-Albright4,5

1 Division of Thoracic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland

2 Division of Medical Oncology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah

3 Division of Public Health, Department of Family & Preventive Medicine, University of Utah School of Medicine, Salt Lake City, Utah

4 Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah

5 George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah

 

ABSTRACT

Background:  The majority of lung cancers are smoking-related, with environment and genetics factors contributing.  The interplay between environmental and genetic contributions in non-smoking-related lung cancers is less clear.

Methods: We analyzed a population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (n=5,544) for evidence of a genetic contribution to lung cancer predisposition in smoking (n=1,747) and non-smoking cases (n=784).  Statistical methods were used to test for significant excess relatedness of cases and estimate relative risk (RR) in close and distant relatives of lung cancer cases.

Results: Significant excess relatedness was observed for all lung cancer cases (p<0.001) and for the subsets of smoking (p<0.001) and non-smoking-related (p<0.001) cases when all pairwise relationships were considered.  Only the non-smoking-related subset of cases showed significant excess relatedness when close relationships were ignored (p=0.020).  First-, second-, and fourth-degree relatives of non-smoking-related lung cancer cases had significantly elevated RR.  An even higher elevated RR was observed for first-, second-, third-, and fourth-degree relatives of smoking-related lung cancer cases.

Conclusions:

Non-smoking-related lung cancer cases show significant excess relatedness for both close and distant relationships, providing strong evidence for a genetic contribution as well as an environmental contribution.  Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution.  Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer.  Screening and gene identification should focus on high-risk pedigrees.

 

 

SUPPLEMENT

Lung cancer is the leading cause of cancer-related deaths worldwide and cigarette smoking is established as the strongest risk factor in its development. However, both environmental and genetic factors may play a role.1,2 There appears to be a 2-fold increase in the development of lung cancer in a patient when a first-degree relative has lung cancer.3-5 Despite this and evidence of familial clustering in close relatives, the possibility of shared environment may partly explain this increase in first-degree relatives.6

Demonstration of a clear genetic contribution to the development of lung cancer would require both an evaluation of risk beyond first-degree relatives and adjustment for smoking. The ability to adjust for smoking would remove the largest confounding variable.

Utilizing a large population database that has genealogical data is imperative to help answer this question. Created in the 1970s using family history from the Family History Library of the Church of Jesus Christ of Latter-day Saints (Mormons), the Utah Population Database (UPDB) is a computerized genealogical record of the Utah pioneers and their descendants.7 This database now has over 7 million unique individuals with some pedigrees extending to 12 generations.

The UPD can be linked to the Utah Cancer Registry (UCR), which has a record of all malignant neoplasms, except squamous and basal skin carcinomas, since 1966 with over 98% follow-up achieved. Smoking status can then be determined from death certificates, as this is a mandatory variable, which go back to 1904. Linking these databases allows selection of matched controls for cases and allowed estimation of cohort specific rates of lung cancer. From this we further selected only individuals that had at least 12 of their 14 immediate ancestors in the genealogy (both parents, all four grandparents, and at least six of their eight grandparents). Then by selecting only cases of lung cancer, we were able to find nearly 19,000 cases, from which 3,170 meet all of the above criteria. Once stratified by tobacco use, leaving 1,747 individuals with smoking-related lung cancer and 784 individuals that died from non-smoking-related lung cancer.

To test for excess relatedness, the Genealogical Index of Familiality (GIF) test was specifically designed for use with the UPD and considers the average pairwise relatedness for a set of individuals. This is accomplished by comparing the average pairwise relatedness for all individuals with lung cancer with their expected average pairwise relatedness in the Utah population, as estimated in 1,000 sets of matched controls. From this, determination of both environmental and genetic contribution can be gleamed. Additionally, relative risk (RR) can be calculated of the observed versus expected number of affected relatives among a set of relatives.

When looking at Figure 1A and Figure 1B we can see differences in the GIF graphs of the smokers (1A) and non-smokers (1B), which are both statistically significant from matched controls. The y-axis shows the contribution to the mean case GIF statistic and the x-axis in the genetic distance of the pair. A genetic distance of 2 is primary siblings, while a genetic distance of 7 is second cousins once removed.

To account for shared environmental factors, all pairwise relationships closer than a genetic distance of 4 (first cousins) are ignored. In the smokers (Fig 1A), the curves are significantly different over the first 3 genetic distances, which may be due to shared environment, but remains significant in distant relationships. Compared to the non-smokers (Fig 1B) where there is an obvious difference at genetic distances greater than 6, thus implying lack of a shared environment and more related to a genetic contribution.

 

fig1aFigure 1A.  GIF analysis for 1,747 smoking-related lung cancer deaths compared to 1,000 sets of matched deceased Utah controls. (The portion of the graph highlighted with the oval demonstrates close relations and are more likely to have a shared environmental contribution).

 

fig1b

Figure 1B.  GIF analysis for 784 non-smoking-related lung cancer deaths compared to 1,000 sets of matched deceased Utah controls. (Compared to Figure 1A, the portion of the graph with the oval highlights distant relations and supports a genetic contribution to the development of lung cancer)

 

 

However, in non-smokers there is still a significant difference in close relationships where the shared environment does not include environmental tobacco smoke. Demonstrating excess relatedness among distant relationships provides strong support for a genetic contribution. The RR estimates for both non-smokers and smokers continued to be significant out to fourth degree relatives. While the RR does decrease with genetic distance, it remains significant. The RR for non-smoking-related lung cancer in relatives of non-smoking-related lung cancer probands is 1.84 for first-degree relatives and 1.79 for second-degree relatives. This drops off to 1.22 for fourth-degree relatives, while still remaining significant. Interestingly, we also asked what is the risk of dying of any type of lung cancer in relatives stratified by the smoking status of the proband relative (Table 1). This differs from dying of the same type (smoking-related or non-smoking-related) of lung cancer as the proband relative. Once this occurs, the individual smoking status of relatives begins to confound results of distant relatives.

 

TABLE 1. Estimates of RR for any lung cancers in relatives stratified by smoking status of the proband relative

tab1

 

An example of a non-smoking-related pedigree from the UPDB is seen in Figure 2.

 

 

SC FIG2

Figure 2: Example of a high-risk non-smoking-related lung cancer pedigree. Founder has over 24,000 total descendants in UPDB.  A total of 7 descendants had non-smoking-related lung cancer in Utah (only descending lines to these cases are shown).  An overall excess of lung cancer was seen with 55 total lung cancer cases observed and 40.2 expected based on cohort specific UPDB rates of lung cancer (p=.015).

 

An interesting finding was the RR of lung cancer in the last spouse of cases with lung cancer. When controlled for smoking, spouses of non-smokers do not develop lung cancer at an increased rate over the expected. However, in those that die of smoking-related lung cancer, the spouse has a 2.7-fold higher rate of the development of lung cancer. This further strengthens the argument of shared environment, with environmental tobacco smoke being the most likely culprit. Also, in smokers, there is a nearly 2.6-fold increase in the development of lung cancer in first-degree relatives of patients with smoking-related lung cancer. This may be due to shared environment, as it is similar to what is seen in spouses, but this continues to be elevated out to fourth-degree relatives where the relative risk is still significant at 1.15. This raises the possibility of a synergistic influence of smoking and genetics with a gene-environment interaction. This theory is supported with genome-wide association studies.8

While these results are exciting, we caution wide spread adoption. The population of Utah is representative of the United States and Northern European descent. With a very homogenous population some may raise the possibility of common genetics. However, it is not inbred and actually has low to normal levels compared to the rest of the United States.9

The importance of this study demonstrates strong supporting evidence for a genetic contribution to non-smoking-related lung cancer. Future directions will focus on evaluating different histologies and other variables that may further help in the refinement of being able to select high-risk patients. Also, these results highlight the importance of determining if a family history is positive for smoking- or non-smoking-related lung cancer. Bearing in mind, that relatives of some smoking-related lung cancer patients may be a predisposition gene carrier, which puts them at even higher risk. Efforts to try and identify lung cancer predisposition genes should focus on the subset of high-risk non-smoking-related lung cancer pedigrees.

 

REFERENCE 

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  7. Skolnick, M. The Utah genealogical database: a resource for genetic epidemiology. Banbury report 4, 285–297 (1980).
  8. Zhang, R. et al. A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 35, 1528–1535 (2014).
  9. Jorde, L. B. Inbreeding in the Utah Mormons: an evaluation of estimates based on pedigrees, isonymy, and migration matrices. Ann. Hum. Genet. 53, 339–355 (1989).

 

SUPPORT

This work was supported  by the Utah Cancer Registry, which is funded by Contract

No. HHSN261201000026C from the National Cancer Institute’s SEER Program with additional support from the Utah State Department of Health and the University of Utah.

Partial support for all data sets within the Utah Population Database (UPDB) was provided by Huntsman Cancer Institute, University of Utah and the Huntsman Cancer Institute’s Cancer Center Support grant, P30 CA42014 from National Cancer Institute.

Lisa Cannon-Albright acknowledges support from the University of Utah Center on Aging and the Huntsman Cancer Foundation.

 

 

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