Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Cancer Med. 2022 Aug;11(15):2896-2905. doi: 10.1002/cam4.4654. Epub 2022 Mar 13.
Smoking has shown interactions with bladder cancer (BC) genetic variants, especially N-acetyltransferase-2 (NAT2), a tobacco smoke metabolism gene, on BC risk. The interactions by disease aggressiveness are unknown.
We investigated the interaction between smoking and 18 single nucleotide polymorphisms (SNPs) for BC, individually and in a genetic risk score (GRS), on urothelial cancer (UC) risk including BC. We analysed data from 25,453 individuals with 520 incident UCs during follow-up, 339 non-aggressive (non-fatal, non-muscle invasive) and 163 aggressive (all other) UCs. Hazard ratios (HRs), absolute risks and additive and multiplicative interactions for two-by-two combinations of never/ever smoking with low/high genetic risk were calculated.
Smoking and NAT2 rs1495741 interacted strongly, positively on aggressive UC on both the multiplicative (p = 0.004) and additive (p = 0.0002) scale, which was not observed for non-aggressive UC (p ≥ 0.6). This manifested in a higher HR of aggressive UC by ever smoking for the slow acetylation NAT2 genotype (HR, 5.00 [95% confidence interval, 2.67-9.38]) than for intermediate/fast acetylation NAT2 (HR, 1.50 [0.83-2.71]), and in differences in absolute risks by smoking and NAT2 genotype. Smoking also interacted additively and positively with the GRS on any UC (p = 0.01) and non-aggressive UC (p = 0.02), but not on aggressive UC (p = 0.1). Gene-smoking interactions of lesser magnitude than for NAT2 were found for SNPs in APOBEC3A, SLC14A1 and MYNN.
This study suggests that smoking increases UC risk more than expected when combined with certain genetic risks. Individuals with the slow acetylation NAT2 variant might particularly benefit from smoking intervention to prevent lethal UC; however, replication in larger studies is needed.
吸烟已显示出与膀胱癌（BC）遗传变异的相互作用，尤其是 N-乙酰转移酶-2（NAT2），一种烟草烟雾代谢基因，与膀胱癌风险有关。疾病侵袭性的相互作用尚不清楚。
我们研究了吸烟与 18 个单核苷酸多态性（SNP）之间的相互作用，这些 SNP 单独作用以及作为遗传风险评分（GRS）在膀胱癌（BC）风险上，包括尿路上皮癌（UC）风险。我们分析了 25453 名个体的随访数据，这些个体在随访期间发生了 520 例 UC 事件，其中 339 例为非侵袭性（非致命性、非肌肉浸润性），163 例为侵袭性（所有其他）UC。计算了从不吸烟/吸烟与低/高遗传风险之间的两两组合的风险比（HR）、绝对风险以及加性和乘法交互作用。
吸烟和 NAT2 rs1495741 在侵袭性 UC 上表现出强烈的、正向的乘法（p=0.004）和加性（p=0.0002）相互作用，但在非侵袭性 UC 上没有观察到（p≥0.6）。这表现为，对于慢乙酰化 NAT2 基因型，吸烟与侵袭性 UC 的 HR 更高（HR，5.00 [95%置信区间，2.67-9.38]），而对于中间/快速乙酰化 NAT2（HR，1.50 [0.83-2.71]），并且吸烟和 NAT2 基因型之间存在绝对风险的差异。吸烟还与任何 UC（p=0.01）和非侵袭性 UC（p=0.02）的 GRS 呈加性和正相互作用，但与侵袭性 UC 没有相互作用（p=0.1）。在 APOBEC3A、SLC14A1 和 MYNN 中的 SNP 中发现了比 NAT2 小的基因-吸烟相互作用。
本研究表明，吸烟与某些遗传风险结合后，会使 UC 风险增加超出预期。具有慢乙酰化 NAT2 变异的个体可能特别受益于吸烟干预，以预防致命性 UC；然而，需要在更大的研究中进行复制。
