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ScienceWeek
MEDICAL BIOLOGY: ON THE ETIOLOGY OF LUNG CANCER
The following points are made by H. Ahsan and D.C. Thomas (J. Am. Med. Assoc. 2004 292:2026):
1) Lung cancer is the number one neoplasm in the world, both in terms of incidence and mortality.[1] The incidence of lung cancer differs by geographic area, sex, age, and over time,[1,2] reflecting the effect of the underlying distribution and trend in use of its principal determinant, tobacco smoking. Although 80% to 90% of lung cancer cases occur in current or past tobacco smokers, only a small fraction of smokers (1%-15%) develop lung cancer,[2] depending on how much and how long an individual has smoked and the presence of other causes of lung cancer.
2) Clearly, because all lung cancers do not occur in smokers and the vast majority of smokers do not develop lung cancer, other etiological factors can independently (in the absence of smoking) or jointly (in conjunction with smoking) cause lung cancer, beyond the purely stochastic nature of the disease process. These factors include genetics (measured as family history),[3.4] arsenic exposure,[5] radiation exposure, and other environmental carcinogens.[2] Although genetic factors probably contribute in all populations, the contribution of other factors is population-specific. For example, in all areas of the world lung cancer shows a modest level of familial aggregation,[2] whereas only in specific environmental, occupational, and therapeutic settings do arsenic and ionizing radiation contribute to lung cancer etiology.[2]
3) Given that tobacco smoking is the overwhelming cause of lung cancer and is prevalent throughout the world, examination of the causes of lung cancer other than tobacco smoking should take tobacco into consideration. Although major genes similar to those for single-gene disorders have yet to be identified for lung cancer, an aggregation of lung cancer in families has long been recognized.[3.4] Between 3% and 6% of all patients with lung cancer have a positive family history of lung cancer.[2] Familial aggregation in the context of lung cancer may be due to shared exposure to tobacco and other lung carcinogens or shared preventive factors within families; major genes (eg, chromosome 6p locus); modifier genes that enhance the carcinogenic potential of tobacco smoking and other occupational and environmental lung carcinogens, including arsenic; addiction genes (eg, nicotine addiction genes) that may predispose individuals to initiate or continue tobacco smoking; and chance.
4) Both shared genes and shared environment can produce detectable familial aggregation in lung cancer. If familial aggregation of lung cancer can be established as an independent phenomenon from familial aggregation of smoking or other lung carcinogens, a genetic etiology for at least a subset of lung cancer cases aggregating within families could be inferred. However, separating the effect of family history from the effect of shared tobacco or other environmental carcinogens is challenging, especially among populations in which such exposures are common.
References (abridged):
1. Ferlay J, Bray F, Pisani P, Parkin D. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. Lyon, France: IARC Press; 2004.
2. Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest. 2003;123(suppl 1):21S-49S
3. Tokuhata GK, Lilienfeld AM. Familial aggregation of lung cancer in humans. J Natl Cancer Inst. 1963;30:289-312
4. Sellers TA, Elston RC, Stewart C, Rothschild H. Familial risk of cancer among randomly selected cancer probands. Genet Epidemiol. 1988;5:381-391
5. Guo HR. Arsenic level in drinking water and mortality of lung cancer (Taiwan). Cancer Causes Control. 2004;15:171-177
J. Am. Med. Assoc. http://www.jama.com
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Related Material:
MEDICAL BIOLOGY OF LUNG CANCER
The following points are made by M.E. Garber et al (Proc. Nat. Acad. Sci. 2001 98:13784):
1) Four main histological subtypes of lung cancer are regularly distinguished by tumor morphology under the light microscope. Squamous and small cell tumors account for approximately 30 percent and 19 percent of all lung cancers, respectively. These cancers are believed to derive mainly from epithelial cells that line the larger airways. Adenocarcinomas comprise 30 percent of all lung cancers, and these tumors are believed to derive from epithelial cells that line the peripheral small airways. Finally, 10 percent of lung tumors are classified as "large cell", a poorly differentiated subtype usually diagnosed by exclusion of the other 3 types of lung cancer. Like adenocarcinomas, large cell tumors are preferentially located in the periphery of the lung.
2) Patients with non-small cell lung tumors (squamous, adenocarcinomas, and large cell) are treated differently from those with small cell tumors. The pathological distinction between small cell lung cancer and non-small cell lung cancer is therefore very important. There is a relative consensus among pathologists on the diagnosis of small cell cancer. These tumors progress along a typical clinical course that is characterized by an excellent initial response to chemotherapy and is often associated with several months of complete regression. This short-term regression, however, is followed by recurrence, development of chemo-resistance, and finally death caused by systemic dissemination. In contrast, the morphological subtyping of non-small cell lung cancer is more difficult and far less reliable in predicting patient outcome. Approximately 50 percent of patients die from metastatic disease even after complete surgical removal of the primary tumor. The initial tumor pathologic diagnosis is based on small bronchoscopic biopsy specimens and may change when surgically removed specimens are reexamined. Lung tumor heterogeneity is well documented and is reflected in the morphological classification of mixed tumors such as adenosquamous carcinoma or combined small cell lung cancer containing both small cell and non-small cell components.
Proc. Nat. Acad. Sci. http://www.pnas.org
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Related Material:
ON MALIGNANT MESOTHELIOMA
The following points are made by M. Carbone and M.A. Rdzanek (Clin Lung Cancer. 2004 Suppl 2:S46):
1) Malignant mesothelioma (MM) is a very aggressive tumor that is caused by environmental, biologic, and genetic factors. Among these factors, asbestos plays a major role. The link between asbestos and MM has been firmly established through numerous epidemiologic studies conducted during the past 40 years. However, the causal role of chrysotile asbestos compared with crocidolite asbestos in MM, the method of correctly establishing asbestos exposure, the amount of asbestos necessary to cause MM, and the mechanisms of asbestos tumorigenicity are still being debated.
2) Along with asbestos, Simian virus 40 (SV40), a DNA monkey virus, has recently been implicated in the etiology of MM. Simian virus 40 large T antigen (Tag) and small t antigen (tag) are largely responsible for the carcinogenicity of the virus, and it is possible that SV40 and asbestos are cocarcinogens.
3) Finally, a genetic factor identified in 3 villages in Cappadocia, Turkey, where 50% of individuals die of MM, appears to be the cause of a high incidence of the disease. In these villages, genetic predisposition for MM works together with erionite, a nonasbestos fiber found in the stones used in construction of houses.
4) The diagnosis of MM is made histologically and confirmed through electron microscopy and immunohistochemistry. Currently available therapies for MM prolong survival by a few months at most. An SV40 vaccine is being developed for human use and it is hoped that it may reduce the incidence of MM in asbestos workers.
Clinical Lung Cancer http://www.asco.org
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