內生性荷爾蒙與未吸菸台灣女性肺腺癌之分子流行病學研究

Abstract

研究背景與目的 肺癌是目前世界上死亡率最高的癌症，而腺癌為女性最好發的組織學形態。絕大部分台灣的女性肺腺癌病患是非吸菸者，顯示可能有吸菸之外的危險因子導致女性肺腺癌的發生。除此之外，吸菸對於女性肺癌的可歸因性更低於男性。因此，比起男性，女性可能對於肺腺癌有較高的易感受性，且荷爾蒙因子應該在肺癌的進程中會扮演一定的角色。過去的研究也指出，在肺腺癌的組織內發現有女性荷爾蒙接受器的表現，所以更進一步顯示內生性的荷爾蒙很可能會參與在肺腺癌的形成過程中。過去研究曾經探索外源性與內生性荷爾蒙和肺癌發生的相關，但研究結論並不一致。這些不一致的結論，可能是因為研究樣本數的大小、肺癌組織學形態的異質性、吸菸情況或不同的荷爾蒙來源而造成。所以，本研究將探討內生性荷爾蒙與其有關的基因，在女性肺腺癌的所扮演的角色。我們收集停經後的女性，並利用病例對照研究方法，試圖了解血液中的荷爾蒙和女性肺腺癌發生的相關，並且評估血液中荷爾蒙是否會與荷爾蒙相關的基因有交互作用。 材料與方法 本研究採用病例對照研究法，並收集187位停經後的女性肺腺癌病患，與248位經年齡配對的健康對照。曾經有吸菸史、荷爾蒙補充療法使用或口服避孕藥使用的個案都被排除在本研究之外。我們測量了血漿中在荷爾蒙生成代謝路徑中的八個性荷爾蒙，包括了estradiol、estrone、progesterone、DHEA、DHEA-S、androstenedione、testosterone與free-testosterone，並分析他們與女性肺腺癌的相關。荷爾蒙生成代謝路徑上的基因多形性包括CYP17 -34 T->C, CYP19 Arg264Cys, CYP1A1 MspI, CYP1A1 Ile462Val, COMT Val158Met, AR-CAG repeat, ERα PvuII與 SRD5A2 Val89Leu，與女性肺腺癌相關的分析也納入在本研究中。我們也更進一步的分析荷爾蒙相關的基因多形性與血漿中荷爾蒙量，對於女性肺腺癌發生可能的修飾作用。本研究利用條件式邏輯斯迴歸分析相關的勝算比與其95%信賴區間。並且，年齡、教育程度、二手菸與身體質量指數(BMI)會納入在迴歸模式內以調整潛在的干擾作用。 研究結果 當血漿estradiol量在中分位(OR, 0.35; 95% CI, 0.2-0.6)或高分位(OR, 0.29; 95% CI, 0.2-0.5)時，相較於低分位，有顯著降低的女性肺腺癌風險。同樣的保護作用也可見於中分位的血漿androstenedione量(和低分位比較之OR, 0.53; 95% CI, 0.3-1.0)，但此作用並不見於高分位的血漿androstenedione量。相較於低分位的血漿DHEA-S量，中分位 (OR, 0.44; 95% CI, 0.3-0.8)及高分位 (OR, 0.57; 95% CI, 0.3-1.0) DHEA-S血漿量，皆有顯著偏低的女性肺腺癌風險。當CYP19 Arg264Cys為A/A基因型時，相較於A/G+G/G基因型，有顯著較低的對於女性肺腺癌風險 (OR, 0.58; 95% CI, 0.34-0.97)。相較於帶有AR(CAG)n的L/S+L/L基因型， S/S基因型有顯著升高的女性肺腺癌風險 (OR, 1.65; 95% CI, 1.06-2.57)。在低estradiol血漿量之女性，帶有ERα PvuII T/T基因型者，相較於帶T/C+C/C基因型者，有較低的女性肺腺癌風險 (OR, 0.52; 95% CI, 0.23-1.16)；但是ERα PvuII T/T基因型的作用，不存在於高estradiol血清量的女性。當androstenedione血漿量偏高時，CYP17 T/C+C/C基因型相較於T/T基因型，有顯著較低的女性肺腺癌風險 (OR, 0.37; 95% CI, 0.19-0.73)；但在androstenedione血漿量偏低時，CYP17 T/C+C/C基因型的作用則不顯著。在體內androstenedione (OR, 1.98; 95% CI, 1.15-3.43)或testosterone (OR, 1.98; 95% CI, 1.15-3.43)血漿量偏高時，AR(CAG)n S/S基因型相較於L/S+L/L基因型，有顯著較高的女性肺腺癌風險；但在androstenedione或testosterone血漿量偏低時，AR(CAG)n 基因型的作用則不顯著。 結論 本研究指出血漿荷爾蒙濃度會影響女性肺腺癌的發生，而且荷爾蒙的合成代謝酵素與其接受器的基因型，則會修飾血漿荷爾蒙濃度的作用。

Background and Specific Aims Lung cancer is the leading cause of cancer death worldwide, and the adenocarcinoma constitutes the predominant histological type among women. Patients with female lung adenocarcinoma (FLAD) are mostly never smokers, which indicate that risk factors other than cigarette smoking may be involved. In light of the attributable fraction of cigarette smoking to lung cancer is considerably lower for lung cancer in females than it is in males. Therefore, women may be more susceptible to lung adenocarcinoma than men are, and hormonal factors may play a role in the development of lung cancer. Previous studies have shown that endogenous hormones such us the estrogen receptor expressed in lung adenocarcinoma tissue suggest that sex steroid hormones may be involved in the carcinogenesis of lung cancer. Although the associations between endogenous and exogenous hormones and lung cancer have been investigated in several studies, the results remained controversial. The interpretability of these findings is limited because of a small sample size, heterogeneous subtypes of lung cancer, smoking status, and hormone exposures from various sources. The aim of this study was to explore the role of endogenous hormones and hormone related genes in FLAD. A case-control study design was employed among postmenopausal women. Two specific objectives were investigated: a) examining the associations between circulating sex steroid hormones and FLAD; b) evaluating the potential effect modifications of plasma hormone levels and hormone related genes in FLAD. Material and Methods A total of 187 patients with FLAD and 248 age-matched healthy control subjects were included in this study. People who had a history of cigarette smoking, hormone replacement therapy, and oral contraceptive were excluded. Several plasma sex hormones, (i.e. estradiol, estrone, progesterone, DHEA, DHEA-S, androstenedione, testosterone, and free-testosterone in the steroid hormone pathway) were used to estimate the potential associations to FLAD. Polymorphisms of hormone related genes (CYP17 -34 T->C, CYP19 Arg264Cys, CYP1A1 MspI, CYP1A1 Ile462Val, COMT Val158Met, AR-CAG repeat, ERα PvuII, and SRD5A2 Val89Leu) were used to assess the effects on FLAD. We further analyzed potential effect modifications between hormone related genes and circulating hormones. A conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs). Age, education, and BMI were adjusted in the regression models. Results The intermediate (OR, 0.35; 95% CI, 0.2-0.6) and highest (OR, 0.29; 95% CI, 0.2-0.5) groups of estradiol levels exhibited significanty reduced risks of female lung adenocarcinoma compared with the lowest group. A significant reduced risk was identified among women with an intermediate androstenedione level compared with the lowest level group (OR, 0.53; 95% CI, 0.3-1.0); a reduced risk was exhibited in the highest level group but the association was significant. Compared with the risk of subjects of the lowest level of DHEA-S, the risks of subjects with an intermediate (OR, 0.44; 95% CI, 0.3-0.8) and the highest (OR, 0.57; 95% CI, 0.3-1.0) levels declined significantly. Patients with A/A genotype of CYP19 R264C exhibited a lower risk (OR, 0.58; 95% CI, 0.34-0.97) of FLAD than those with the A/G+G/G genotype. Women with the S/S alleles of AR(CAG)n exhibited a higher risk (OR, 1.65; 95% CI, 1.06-2.57) than those with either one or two L allele. Furthermore, the T/T genotype of ERα PvuII exhibited a borderline reduced risk to T/C+C/C genotype among women with a low estradiol level (OR, 0.52; 95% CI, 0.23-1.16), whereas the association did not exist among women with a high estradiol level. The T/C+C/C genotype of CYP17 was associated with FLAD compared with the T/T genotype among women with a high androstenedione level (OR, 0.37; 95% CI, 0.19-0.73); however, the association was not detected in subjects with a low androstenedione level. In addition, the S/S genotype of AR(CAG)n was found to be associated with a higher risk of FLAD among women with a high androstenedione level (OR, 1.98; 95% CI, 1.15-3.43), and among women with a high testosterone level (OR, 1.88; 95% CI, 1.09-3.26), whereas the association of the S/S genotype with FLAD was not exhibited in women with a high level of either androstenedione or testosterone women. Conclusion Our findings indicated that the circulating sex hormones may play a pivotal role in the etiology of lung adenocarcinoma among postmenopausal women. Hormone related genes might interact with sex steroid hormones affecting the risk of FLAD.