Genetics can't be ignored in lung cancer development
By V. UPENDER RAO
Published June 6, 2005
The dogma that smoking and smoking alone causes lung cancer has prevailed over the clinicians and lung cancer researchers for many years. This, in spite of the glaring fact that only 1 to 15 percent of smokers develop lung cancer and a good 10 percent of lung cancer patients have never been smokers.
Genetic predisposition to lung cancer has been studied, and familial aggregation has been observed. Shared addiction to nicotine and exposure to secondhand smoke could explain familial clustering without a genetic basis and cancer among nonsmokers. Previous studies did not separate the relative risk from cigarette smoking and other environmental factors from that attributable to genetic cause.
A study that appeared in the Dec. 22/29 issue of the Journal of the American Medical Association examined the risks conferred by genetics and cigarette smoking separately. The study consisted of a linkage analysis of all cases of lung cancer diagnosed in Iceland between Jan. 1, 1995, and Feb. 28, 2002.
A nationwide search of the genealogical records of all living Icelanders and the majority of their ancestors since their initial settlement in Iceland in 870 A.D. was conducted. This allowed an examination of all lung cancer cases and their relationships recorded in the Icelandic Cancer Registry.
It facilitated the evaluation of cancer in second and subsequent generations and the elimination of shared environmental cause because of the movement of subsequent generations away from the extended family unit.
The study results revealed the following:
--The first-, second- and third-degree relatives of lung cancer patients were at a significant risk for lung cancer independent of cigarette smoking and other environmental factors.
--The risk was strongest for the relatives of patients who developed lung cancer before age 60.
--There was an increased relative risk for the spouses of patients indicating shared environmental cause in addition to possible nonrandom or consanguineous mating.
--The increased relative risk among distant relatives living away from the nuclear family makes shared environmental factors less likely and genetic factors more likely in the causation of lung cancer in these families.
--Adenocarcinoma was more prevalent in these families as opposed to other major histological types of lung cancer. It is an established observation that adenocarcinoma is not strongly associated with smoking. This further indicates, although indirectly, that causes other than smoking were operative in these families.
--Segregation analysis indicates a rare major autosomal dominant gene as the cause of lung cancer in these families. High prevalence of polymorphisms in this gene explains the variation in the individual susceptibilities to environmental carcinogens.
In conclusion, this is the first study that has used extensive genealogical database and examined the role of smoking. Its results strongly suggest a genetic predisposition to lung cancer in relatives of patients with lung cancer. However, cigarette smoking is an important carcinogen, and the inherited polymorphisms (variation) of the causal gene and other promoting and supporting genes collectively determine the degree of individual susceptibility to lung cancer.
Since 90 percent of all lung cancer patients are current or former smokers, complete smoking cessation should eliminate 90 percent of lung cancers. This, however, is an extrapolated assumption and not a scientific fact, but it could serve as a good public health message.
--V. Upender Rao, MD, FACP, practices at the Cancer and Blood Disease Center in Lecanto.