Family History of Lung Cancer Doubles Risk for the Disease

TOKYO, Oct. 10 -- A history of lung cancer in a first-degree bestows nearly twice the risk of developing the disease, according to researchers here.

The association was also stronger in women than in men and in never-smokers versus current smokers Manami Inoue, M.D., Ph.D., of the Japanese National Cancer Center, and colleagues, reported in the October issue of CHEST. Yet the association between smoking and the family history of lung cancer was not clear.

"To our knowledge, this is the first prospective cohort study of this association in Japan," which also has a markedly high incidence of non-smoking lung cancer, they wrote.

To clarify a possible hereditary predisposition to lung cancer, the researchers studied 102,255 middle-age and older participants (48,834 men and 53,421 women) with a 13-year follow-up. The participants came from two cohorts, 1990 and 1993-1994, in the Japan Public Health Center study.

A total of 791 cases of lung cancer were newly diagnosed during the follow-up. Smoking habits were classified as current, former, and never.

An almost twofold increased risk of lung cancer developed in those with a family history of the disease in a first-degree relative (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.31 to 2.88).

The risk was greater in women (HR, 2.65; CI, 1.40 to 5.01) than in men (HR, 1.69; CI, 1.03 to 2.78), even though only 9% of the women were ever-smokers, compared with 76% of the men.

With regard to histologic type, a positive family history of squamous cell carcinoma was more strongly associated with an increased risk of lung cancer (HR, 2.79; CI, 1.37 to 5.68), compared with other histologic types such as adenocarcinoma and small-cell carcinoma where no clear increase in risk was observed.

However, a family history of overall cancer was not associated with an increased risk of lung cancer compared with the risk for those who had a family member with lung cancer.

The association with family history was notably higher in never-smokers (HR, 2.48; CI, 1.27 to 4.84) than in current smokers (HR, 1.73; CI, 0.99 to 3.00).

The role of smoking in this scenario remained something of a conundrum, however. Although no significant interaction between smoking status and lung-cancer family history was detected, the researchers reported that among current smokers, the lung cancer risk was significantly increased only in those in the highest-pack-year category. In addition, an increase in lung cancer risk for current smoking and increased pack-years was observed regardless of the family history of lung cancer.

Commenting on this finding, the researchers said that smoking is the most important environmental risk factor for lung cancer, and the association between a person's smoking habit and that of parents or siblings has been well described. Yet the relationship between family history of lung cancer, smoking, and lung cancer is still "unresolved." Further studies are needed, they wrote, "to clarify if there is an effect modification between family history of lung cancer and smoking."

Describing a number of study limitations, the researchers cited the fact that participants provided information on family history, but diagnoses were not verified through medical sources or health records. The possibility of random misclassification of this information in subjects with or without subsequent lung cancer exists and may have led to an underestimation of true risk.

Further limitations are the lack of information on family size and age of relatives, raising the possibility of bias in calculations of familial risks.

Commenting on their findings, the investigators said that the familial risk of lung cancer documented in previous studies may have been due not only to shared environmental factors, but also to a hereditary predisposition. Studies suggest that the long-held belief that lung cancer is not hereditary may in fact be wrong, and that heredity may be at least in part causative, Dr. Inoue's team stated.

In the present study, overall lung cancer incidence in a first-degree relative was associated with a 95% increase in lung cancer on 13 year follow-up, the researchers wrote. These, and other similar findings, support the hypothesis that genetic susceptibility to lung cancer might act as both an independent risk factor and an effect modifier of environmental risk factors.

As understanding of the human genome develops, molecular epidemiologic studies may identify genes that influence the development of this condition, and correspondingly help identify the etiology of nonsmoking lung cancer, which is common in Japan, Dr. Inoue said.

In conclusion, the team wrote, "Our results suggest that those with a family history of lung cancer are more likely to acquire lung cancer themselves, although further studies are needed to clarify the role of family history of lung cancer and smoking."

In an accompanying editorial, Ann G. Schwartz, Ph.D., of Wayne State in Detroit, wrote that the first reports of the role of "familial aggregation" in lung cancer were published more than 40 years ago. In lung cancer, familial aggregation is a hallmark for inherited susceptibility, particularly when familial clustering of shared environmental factors, such as smoking, can be ruled out, she wrote.

This prospective study of the two very large Japanese cohorts allowed for the enumeration of family history before the actual lung cancer diagnosis, which minimized recall bias, Dr. Schwarz wrote. A positive family history suggests a role for inherited susceptibility, and the male-female gender difference by smoking exposure suggests that genetic susceptibility to lung cancer is likely to be modified by environmental exposures, she said.

The lung cancer community would benefit from a risk prediction model based on age, race, sex, family history, smoking history, and pulmonary function, Dr. Schwartz wrote. Such estimates could be used in counseling patients and targeting groups for inclusion in screening and prevention trials.

Although smoking prevention and cessation will have the biggest impact on reducing mortality from lung cancer in the long term, in the U.S., there are still an estimated 46 million former smokers and 45.8 million current smokers at risk today, she noted.

"Research focused on screening, early detection, and prevention must continue," Dr. Schwartz said. "Family history should be used as another marker of 'high risk' for lung cancer in spiral CT screening studies and chemoprevention trials," she advised. In addition, she said, family history should be used as a motivational tool for smoking cessation.