First-degree relatives of lung cancer patients have a 2 to 3.5 times greater risk for lung cancer than the general population, and tobacco smoke plays a major role, even among those with a genetic predisposition, according to an article in the December 22nd issue of the Journal of the American Medical Association.

In a second article, Chinese researchers found that people with higher arsenic exposures in water had significantly higher risk for lung cancer, even after adjustment for other risk factors including smoking. The two articles point out the evolving understanding of the interactions among genetics and environmental factors in pathogenesis of lung cancer.

In the first article, Steinn Jonsson, MD, and his Icelandic colleagues examined the contribution of genetic factors to development of lung cancer in Iceland. The risks for developing lung cancer for first-, second-, and third-degree relatives of patients with lung cancer were estimated by linking records from the Icelandic Cancer Registry of all 2,756 patients diagnosed with lung cancer within the Icelandic population from January 1, 1955, to February 28, 2002, with an extensive genealogical database containing all living Icelanders and most of their ancestors since the settlement of Iceland.

The risk for smoking was similarly estimated using a random population-based group of 10,541 smokers from the Reykjavik Heart Study who had smoked for more than 10 years. Among smokers, 562 people developed lung cancer based on lung cancer registry data.

“The nationwide genealogy database used in our study provided a means for uncovering the familial component by revealing more connections between patients, missed in most other populations,” the authors wrote.

A familial factor for lung cancer was shown to extend beyond the nuclear family, as evidenced by significantly increased risks for first-degree relatives (for parents: 2.7 times increased risk; for siblings: 2.02 times increased risk; and for children: 1.96 times increased risk); second-degree relatives (for aunts/uncles: 1.34 times increased risk; and for nieces/nephews: 1.28 times increased risk); and third-degree relatives (for cousins: 1.14 times increased risk) of patients with lung carcinoma. This effect was stronger for relatives of patients with early-onset disease (age 60 or younger at onset) (for parents: 3.48 times increased risk; for siblings: 3.30 times increased risk; and for children: 2.84 times increased risk).

“… this risk ratio [RR] increase in first-degree relatives of patients with lung carcinoma is the result of a combination of environmental, genetic factors, or both. Using genealogy, our study goes further than other reported studies by demonstrating that this familial factor extends beyond the nuclear family as evidenced by significantly increased risk ratio for second- and third-degree relatives of patients with lung carcinoma. In the more distant relationships, shared environmental factors are likely to be of less significance, providing a stronger evidence for genetic factors given that risk ratio is in excess,” they added.

“… although the results presented here support a role for genetics in the risk of lung carcinoma, it should be emphasized that tobacco smoke plays a dominant role in the pathogenesis of this disease, even among those individuals who are genetically predisposed to lung carcinoma,” the authors concluded.

In the second article, researchers found that residents of Taiwan who consumed drinking water with high levels of arsenic have a higher risk of lung cancer, with cigarette smokers from this group having an even greater risk.

Arsenic is a naturally occurring element in soil, and can contaminate drinking water, according to background information in the article. Residents of the southwestern and northeastern coasts of Taiwan had been drinking well water contaminated with a high concentration of arsenic before the establishment of the public tap water system.

Chi-Ling Chen, PhD, and colleagues conducted a study to determine the dose-response relationship between ingested arsenic and lung cancer risk and the added effect of cigarette smoking on this risk.

The study included 2,503 residents in southwestern and 8,088 in northeastern arsenic-endemic areas in Taiwan, who were followed for an average of 8 years. Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire interview.

During the study follow-up period, there were 139 newly diagnosed cases of lung cancer. Residents with the highest level of arsenic exposure had a 3.29 times increased risk for lung cancer, after adjusting for various factors including age, sex, and cigarette smoking status at recruitment. Among nonsmokers, those who were exposed to the highest arsenic level had about 2 times the risk for lung cancer compared with those with the lowest level of exposure. Among participants with the lowest arsenic level, those who had the highest cumulative cigarette smoking exposure had a 4-fold risk of lung cancer compared with nonsmokers. When compared with nonsmokers with the lowest levels of arsenic exposure, those who consumed well water with the highest arsenic levels and smoked for more than 25 pack-years had a more than 11-fold risk of lung cancer.

“Approximately 32 percent to 55 percent of lung cancer cases were estimated to be attributable to the combined effect of cigarette smoking and ingested arsenic, depending on the levels of both exposures,” the authors wrote. “The synergy indices ranged from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smoking on lung cancer.”

“The reductions in cigarette smoking would likely reduce the lung cancer risk accompanied by exposure to arsenic, and similarly, reductions in arsenic exposure would reduce the lung cancer risk among cigarette smokers. Appropriate public health interventions, such as cigarette smoking cessation programs and reduction in arsenic concentration of drinking water, are warranted. Furthermore, it is essential to take cigarette smoking into consideration in the risk assessment and the determination of the maximal contamination level of arsenic in drinking water,” the authors concluded.

In an accompanying editorial, Habibul Ahsan, M.D., MMedSc, and Duncan C. Thomas, PhD, commented on the two lung cancer studies.

“Irrespective of the roles of familial aggregation and environmental exposures to arsenic or other carcinogens, lung cancer is primarily caused by tobacco smoking - an exposure that is largely preventable. If nicotine addiction genes or modifier genes play roles in subsets of patients with lung cancer, such cases can be prevented by preventing tobacco smoking. Although there are no addiction genes for arsenic or other environmental exposures, modifier genes could modulate the effects of these nontobacco carcinogens. Such genes, in combination with major genes, could lead to familial aggregation.”

“Innovative epidemiological studies to detect and separate these effects, taking the lead from studies like those of Jonsson et al and Chen et al, need to be designed in the future. Even for individuals with such a familial risk, or for those who are already chronically exposed to arsenic or other lung carcinogens, avoiding tobacco smoking remains the most feasible option for reducing lung cancer risk,” they wrote.