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    • Mechanisms of increased lung cancer susceptibility independe

    2018-10-30

    Mechanisms of increased lung cancer susceptibility independent of smoking quantity for individuals with chromosome 15q25.1 high-risk genotypes are not entirely clear. Multiple studies have demonstrated associations between SNPs in chromosome 15q25.1 and lung cancer in nonsmokers (Hung et al., 2008; Shiraishi et al., 2009). Functional studies have shown that a gene in this region (PSMA4) has been associated with cancer cell proliferation and apoptosis (Liu et al., 2009) and another gene (IREB2) (Fehringer et al., 2012) has been associated with lung cancer risk. A SNP (rs3813570) in the PSMA4 gene approached genome-wide significance in the STOMP Consortium meta-analysis and a variant in IREB2 (rs17405217) was associated with lung cancer risk in the present investigation and others (Walsh et al., 2013; Walsh et al., 2012). It is therefore possible that the high degree of linkage disequilibrium between chromosome 15q25.1 variants in cholinergic TH-302 associated with increased smoking intensity and those in neighboring genes linked to tumor proliferation may result in frequent haplotypes capturing both heightened cigarette exposure and susceptibility to lung cancer pathogenesis. However, additional research is needed to confirm mechanisms of potential concomitant dual risk of exposure and cancer susceptibility. It is worth noting that pack-years were not associated with the genotypes tested and this variable did not interact with genotype to predict lung cancer risk in either study population. While this may be the result of a combination of lack of sensitivity due to recall bias and sample size (Castaldi et al., 2011), a previously published study of smoking persistence in African-Americans examined pack-years of exposure, accounting for periods of non-smoking, and reported multiple statistically significant associations with SNPs in the 15q25.1 region (Hamidovic et al., 2011). Thus, it is not entirely clear why this measure of smoking exposure was not robust in our investigation. However, given pre-clinical evidence of much higher nicotine self-administration in CHRNA5 knockout mice (Fowler et al., 2011; Fowler et al., 2013; Fowler and Kenny, 2014), it is possible that humans with altered CHRNA5 expression possess a phenotype of markedly greater alveolar tobacco smoke exposure vis-à-vis increased smoking quantity, intensity and puff volume over a lifetime (Ware et al., 2012), which in turn portends greater overall exposure than can be captured with granularity using the measured phenotypes of pack-years or average CPD. This study has some limitations. While we did have sufficient statistical power in an a priori power analysis to detect effects sizes of at least 2.1 (assuming power>.8, allele frequencies ≥0.15 and at least 85 lung cancer cases), in analyses not corrected for multiple comparison, adjusting for multiple comparisons may limited our ability to detect statistically-significant effects robust to multiple corrections. We did not have access to spirometry or diagnostic data for conditions such as COPD and emphysema to enable analyses of potential mediating effects of smoking quantity on the relationship between the CHRNA3-A5-B4 locus and lung cancer risk, which has been demonstrated in European-ancestry studies (El-Zein et al., 2012). Another limitation of the present investigation is that the WHI SHARe analyses did not include males. However, we previously published a genome-wide meta-analyses of smoking quantity that included both genders of African-Americans that confirmed rs2036527 in association with CPD after adjusting for gender (David et al., 2012), but nonetheless, we cannot rule out the possibility that other SNPs nominally associated with CPD in this investigation could be moderated by sex. In addition, we did not have information on type of cigarettes smoked such as menthol cigarettes, smoking topography or plasma cotinine levels. However, two earlier investigations of genetic predictors of lung cancer risk in African-Americans by Amos and colleagues did not show any differential effect of menthol on the relationship between SNP and lung cancer risk (Walsh et al., 2013; Amos et al., 2010).