Why Have We Failed to Find the Low Penetrance Genetic Constituents of Common Cancers?
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1544 Vol. 11, 1544–1549, December 2002 Cancer Epidemiology, Biomarkers & Prevention Commentary Why Have We Failed to Find the Low Penetrance Genetic Constituents of Common Cancers? Neil E. Caporaso1 the BRCA mutations and breast cancer) only explain a fraction Genetic Epidemiology Branch, National Cancer Institute, Rockville, Maryland of the genetic component of risk. 20892 The earliest studies to evaluate candidate genes and tobacco-related cancers began in the pregenotyping era (i.e., Introduction before 1998). Probe drugs corresponding to potentially carci- Despite widespread enthusiasm for the candidate gene ap- nogenic compounds metabolized by the genes of interest were proach to identify common but “low penetrance” susceptibility administered and “metabolic phenotypes” constructed based on genes that predict cancer risk (1), in the aggregate, association the distribution of recovered metabolites; genotypes were in- studies involving complex diseases have yielded a scant harvest ferred. Of the first four metabolic polymorphisms studied by (2). One review concluded recently that only 6 of 166 disease this approach (9–12), only one association can be considered associations that were studied three or more times were repli- well established. Mechanistic (13) and population data (14) are cated consistently (3). Another systematic review of genetic reasonably concordant, and establish that NAT2 “slow acety- polymorphisms and breast cancer could not exclude a potential lators” exhibit increased risk for bladder cancer. Evidence that role for a variety of candidates but neither could it verify polymorphisms in CYP1A1, GSTM1, or CYP2D6 influence significant risk associated with any specific gene (4). Earlier susceptibility to lung cancer remains controversial. For the first studies, as well as meta-analyses involving putative suscepti- two, mechanistic evidence is convincing (15), but meta-analy- bility genes and lung cancer have been inconclusive. Therefore, ses now including a substantial number of studies exhibit only uncertainty as to whether polymorphic variation in the MPO2 weak evidence for a small effect (16–18). For CYP2D6, both gene alters susceptibility to lung cancer is more typical rather mechanistic evidence and population data are null to weakly than unique, and we need to examine the issue in a broad suggestive (19). context. This provides an opportunity to consider why well- conducted studies such as the reports by Feyler et al. (5) and Xu Why Is It Important to Identify Low Penetrance Genes et al. (6) involving the relationship of the MPO gene polymor- That Contribute to Cancer? phism and lung cancer arrive at seemingly opposing conclu- Given that the environment plays a dominant role in most sions. common cancers (20, 21), why is identifying a “minor” genetic I will frame the discussion of the genetics of complex component important? The history of epidemiology indicates disease as pertains to cancer in general and MPO and lung that progress in prevention (i.e., public health) and treatment cancer in particular around the following questions. (i.e., clinical) of cancer can occur without knowledge of the Is there sound evidence that a hereditary component of specific mechanism (or genes) that contribute to susceptibility. common malignancies exist? However, for many malignancies, substantive advances in both If inherited susceptibility to common cancers exists, is it etiologic understanding (i.e., brain and prostate) and in therapy important to identify? (i.e., lung) have been elusive. Given the slow progress, im- What does the current evidence indicate? proved insight from understanding how genes promote or block If finding genetic susceptibility factors is important, why cancer can be crucial. Moreover, even a modest contribution of after more than a decade of work has it not clearly identified? a common genetic factor would imply a substantial attributable What can be done to resolve the question? risk (22). A clear understanding of one or more susceptibility genes could provide improved mechanistic insight, clues to Evidence for an Influence of Heredity in Common Cancers exposure mechanisms (i.e., a gene clearly related to suscepti- The preponderance of evidence from diverse approaches sup- bility may suggest a specific etiologic agent), or may suggest a ports at least some hereditary component for virtually all of the target for chemoprevention or other interventions. Even more major malignancies. Approaches include enumerating cancer in importantly, such a finding can be seen as key to elucidating a relatives of cases compared with the relatives of controls and fundamental question about cancer. Given that on the popula- twin studies that show enhanced concordance in monozygotic tion level, most cancer depends on environmental factors, but compared with dizygotic twins (7, 8). The high penetrance on a cellular level, genetic lesions characterize cancer, under- genes that create striking familial aggregations of cancer (i.e., standing how these two processes intersect will be of funda- mental importance. This is true even if in most instances, hereditary susceptibility genes are not the same as the genes Received 8/28/02; accepted 8/28/02. somatically mutated. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. What Does the Evidence Suggest and Do the Classic 1 To whom requests for reprints should be addressed, at Genetic Epidemiology Criteria for Evaluation of Causality Help? Branch, National Cancer Institute, EPS 7116, 6120 Executive Boulevard, Rock- ville, MD 20892. What can we conclude from the published MPO/lung cancer 2 The abbreviation used is: MPO, myeloperoxidase. studies, and what are the implications for the broader literature? Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2002 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1545 One starting point is to consider the major criteria for the Perspectives on Nonconfirmation? evaluation of causality (23, 24) that include biological plausi- Methodologists from different disciplines have offered diverse bility, strength and specificity of the association, temporality, perspectives on the reasons why verification of gene-disease and dose response. associations has been so inconsistent. Biological Plausibility. MPO is an enzyme that generates re- Virtually all of the observers note that power has been active oxygen species and thereby contributes to bactericidal inadequate, particularly for interactive effects (i.e., gene-envi- activity in white cells. The cost of enhanced killing by the more ronment and gene-gene; Ref. 39). Although population strati- active forms of MPO is increased inflammation, and the bal- fication is both a real and theoretical problem, recent work ance of polymorphic gene variants that alter activity likely suggests it does not pose a substantial source of bias sufficient reflect selection pressure in different populations. In a manner to justify the inefficiency and other drawbacks of using family similar to other polymorphic Phase I enzymes (i.e., CYP1A1), controls in population study settings (40). MPO converts polycyclic hydrocarbons such as benzo(a)pyrene Epidemiologists and statisticians have described poor con- to DNA-binding intermediates (25) potentially contributing to trol selection, design flaws, publication bias, disease misclas- pulmonary carcinogenesis, as well as to other conditions such sification (“phenotype” definition in genetics parlance), failure as arteriosclerosis and Alzheimer’s (26). A G-463-A variant in to obtain or poor quality exposure data, misclassification bias, the promoter region of MPO alters an SP1 binding site and excessive type 1 errors (false-positives), post-hoc and subgroup analysis, and multiple comparisons as the likely culprits (41, results in decreased transcriptional activity. One report suggests 42). Geneticists point to failure to consider the mode of inher- the action of MPO is additionally catalyzed by nicotine, sug- itance, genetic and disease heterogeneity, failure to account for gesting the possibility of enhanced effect in smokers (27). The the linkage disequilibrium structure of the gene, inadequate evidence for biological plausibility is generally supportive. characterization of the mutations that account for the genetic Strength of Association. Before the studies in the current abnormalities, and the likelihood that genes identified only issue, the hypothesis of an association between an MPO variant account for a small proportion of the variability in risk, i.e., and lung cancer has been addressed in six published studies: power (43–45). London et al. (28), LeMarchand et al. (29), Cascorbi et al. (30), All of the above points are relevant; however, it may be Schabath et al. (31), Misra et al. (32), and Kantarcci et al. (33). that additional sources of complexity add to the challenge of A detailed quantitative treatment of the data from all of the identifying the specific genes that account for susceptibility to previous studies involving MPO and lung cancer exceeds the cancer. Three types of complexity will be considered. scope of this article but considering the six earlier published studies, a summary risk ratio is 0.92 (95% confidence interval, Pheotype Complexity 0.75–1.04) for heterozygotes and 0.66 (0.36–0.78) for AA homozygotes with