We read with great interest the study by Lee et al. [1] recently published in Annals of Oncology, in which the association of KRT81 rs3660 (G/C) with survival of nonsmall-cell lung cancer (NSCLC) was reported. Specifically, Lee and colleagues found that patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with the GG genotype [1]. To the contrary, an earlier paper by Campayo et al. [2] reported that the KRT81 rs3660 CC genotype was associated with shorter time to NSCLC recurrence compared with CG + GG.
Single-nucleotide polymorphisms in miRNA binding sites (miR-SNPs) can strengthen or reduce binding between a miRNA and its mRNA target [3]. Our laboratory has focused on the association of miR-SNPs with lung cancer risk [4]. As an extension of that latest study, we genotyped rs3660 in 312 NSCLC cases and 311 population controls frequency matched to cases by age and gender. Consistent with Campayo et al. [1] we found that rs3660 GG (and CG) were associated with reduced risk of cancer-associated mortality compared with CC. However, we observed this association only in men [hazard ratio (HRCG versus CC): 0.51, 95% confidenc interval (CI) 0.29–0.89, P = 0.018; HRGG versus CC: 0.50, 95% CI 0.26–0.98, P = 0.043] and not in women (HRCG versus CC: 1.34, 95% CI 0.73–2.44, P = 0.260; HRGG versus CC: 1.17, 95% CI 0.61–2.24, P = 0.752) (adjusted for age, gender, race, smoking status, pack-years of smoking, stage and histology) (Figure 1). Additionally, we found that rs3660 GG was associated with reduced risk of NSCLC, again only in men (ORGG versus CC: 0.43, 95% CI 0.21–0.87, P = 0.020) compared with women (ORGG versus CC: 1.82, 95% CI 0.80–4.14, P = 0.154) (adjusted for age, gender, race, smoking status and pack-years of smoking).
Figure 1.
Kaplan–Meier survival analysis of rs3660 in (A) men and (B) women with NSCLC.
We note with interest that both the Discovery and Validation cohorts analyzed by Lee et al. comprise 76% and 71% male cases, respectively [1]. In addition, we note that the study population in the study by Campayo et al. was 88% male [2]. Thus, we hypothesize that gender is a modifying factor of the association between rs3660 and NSCLC, which became apparent upon stratification of our samples by gender in the context of a well-matched case–control study. Further, we present additional insight suggesting that this gender-specific association also extends to cancer risk.
Regarding the discrepancy with Lee et al. [1], we also note that the studies in agreement both comprised participants with similar ethnic background, i.e. Caucasian, in which the allelic frequencies of rs3660 C are 47% (our study) and 49% (Campayo et al.), whereas the new study comprises participants of Asian ethnicity, in which the frequency of rs3660 C is 24%.
funding
This work was supported by the intramural program of the National Cancer Institute.
disclosure
The authors have declared no conflicts of interest.
references
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