肺腺癌病人EGFR突變與HMGB1基因多型性的關聯

高遷移率族蛋白1 (High-mobility group protein box 1; HMGB1)在非小細胞肺癌(non-small-cell lung cancer; NSCLC)的病人是一個預後因子。表皮生長因子受體 (Epidermal growth factor receptor; EGFR)突變則在NSCLC的進展扮演重要角色。先前已有許多文獻針對HMGB1之基因多型性(single nucleotide polymorphism; SNP)與癌症或疾病之間的關聯性進行研究，但HMGB1之基因多型性與NSCLC的相關性卻完全無文獻探討。因此，本篇研究中，我們擬觀察HMGB1之基因多型性與非小細胞肺癌之臨床病理特徵的相關性。本篇研究共收集了280個非小細胞肺癌的病人，透過即時聚合酶連鎖反應 (real-time polymerase chain reaction; real-time PCR) 分析了HMGB1 rs1412125、rs2249825、rs1045411以及rs1360485等四組基因多型性。我們發現在調整了其他共變數後，跟wild-type homozygote的病人來比較，那些有抽菸且同時有特定HMGB1 heterozygotes基因型的NSCLC病人(分別是CG、CT、TC在rs2249825、rs1045411、rs1360485中)，比較不會有EGFR的突變。此外，EGFR 熱點突變(hotspot mutation)，即exon 19 in-frame deletion與rs2249825的CG及CG+GG基因型間有顯著的負相關。而在有EGFR突變種的病人中，跟TT homozygotes的病人比，帶有HMGB1 rs1360485 C基因(TC+CC)的病人有比較高的風險得到分化不良的癌型態(odds ratio=5.493，95%信賴區間: 1.130~26.696，p=0.019)。總而言之，我們的實驗結果顯示在有抽菸的NSCLC病人中，HMGB1的變異和EGFR突變有顯著的負相關。HMGB1的變異和抽菸的習慣有可能會影響NSCLC的病理發展。

High-mobility group protein box 1 (HMGB1) is overexpressed and reported to be a prognostic factor in patients with non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutants play an important role in NSCLC progression. Dysregulation of HMGB1 single-nucleotide polymorphism (SNP) may be associated with susceptibility to various cancers or diseases. However, no study has investigated the involvement of the SNP of HMGB1 in NSCLC. In the current study, we focused on examining HMGB1 SNP to elucidate NSCLC clinicopathologic characteristics. The HMGB1 SNPs rs1412125, rs2249825, rs1045411 and rs1360485 were analyzed by real-time polymerase chain reaction in 280 patients with NSCLC. We found that after adjusting for other covariates, NSCLC patients who smoked and who respectively had CG, CT, and TC heterozygotes of HMGB1 rs2249825, rs1045411, and rs1360485, were at lower risk of developing mutant EGFR, compared to those patients with wild-type homozygotes. Moreover, significant inverse associations between the CG and CG + GG genotypes of HMGB1 rs2249825 and the EGFR hotspot mutation, an exon 19 in-frame deletion, were also observed among NSCLC patients. Within patients harboring mutant EGFR, HMGB1 rs1360485 C (TC + CC) allele carriers were at higher risk of developing poorly differentiated cancer types (odds ratio=5.493, 95% confidence interval: 1.130~26.696, p=0.019), compared to patients with TT homozygotes. In conclusion, our results suggested that HMGB1 variants are significantly inversely associated with EGFR mutations among NSCLC patients who smoked. HMGB1 variants and tobacco consumption might contribute to the pathological development of NSCLC.