研究背景：頭頸部鱗狀細胞癌是有著高盛行率的惡性腫瘤疾病，這類病人常併發食道鱗狀細胞共同癌，稱為上呼吸消化道共同癌。導致上呼吸消化道共同癌的主因是由於相似的致癌物接觸，例如抽菸、喝酒等。食道共同癌的發生不但造成治療上的困難，同時這樣的病人也較僅有單一癌症者有著顯著較差的預後。因此如何及早發現有無共同癌是相當重要的。抽菸、喝酒以及頭頸癌的位置早已被確認是共同癌發生的危險因子。此外，近來研究顯示，過多的調節性T細胞浸潤與許多癌症的產生有關，包括上呼吸消化道共同癌。FOXP3是調控調節性T細胞發育及功能的主要蛋白。因此本研究旨在探討FOXP3的基因多型性是否和調節性T細胞的異常浸潤、頭頸癌病人發生食道共同癌的風險、以及患者預後有關。
研究方法：我們連續收錄了在2009-2016年間在成大醫院以及義大醫院進行上消化道內視鏡共同癌篩檢的頭頸癌病患，並詳細的記載其基本資料，包括抽菸、喝酒以及頭頸癌的位置。我們從Hapmap資料庫中找出足以代表FOXP3基因多型性的tag-SNPs (包括 rs2232365，rs3761548，rs3761549)。從病人的周邊血液白血球分離出DNA，然後利用real-time PCR的方式檢測tag-SNPs的基因型。並以免疫組織染色法評估調節性T細胞浸潤於腫瘤的程度。近一步分析FOXP3 tag-SNPs的基因型和上呼吸消化道共同癌的發生、預後、以及調節性T細胞浸潤程度的相關性。
結果：經過配對抽菸、喝酒的狀態且排出女性病患後(因女性病患極少)總共有270位病患被納入分析(包括135位單純頭頸癌患者，以及135位有食道共同癌患者)。從基本資料分析中可以發現頭頸癌的位置(下咽)與共同癌的發生有顯著相關 (p=0.012,勝算比=1.87)。在基因多型性的分析發現，在位點rs3761549帶有 G 基因型會增加2.21倍共同癌的風險(p= 0.009, 95% 信賴區間為 1.22-4.00)，即使經校正頭頸癌位置以及分期後，仍能達到2.10倍的風險增加(p=0.024, 95%信賴區間為 1.11-4.00)。在其他的位點上(rs3761549以及rs2232365) 則無顯著差異。但當我們結合三個位點做haplotype分析可以發現，帶有haplotype C-G-A (rs2232365/ rs3761548/ rs3761549)會降低共同癌發生的風險(p=0.009)。而在位點rs3761549帶有G 基因型的病患，其腫瘤組織中的調節性T細胞的數量顯著較多 (A基因型 : G基因型 = 36.39 : 55.93 個/平方毫米，p = 0.008)。而在存活分析中rs3761549帶有G基因型之晚期 (III和IV) 頭頸癌患者有預後較差的趨勢。 (G基因型 : A基因型，平均存活 41.5月 +/- 3.6月 : 46.6月 +/- 5.1月, p = 0.370)
結論：男性頭頸癌患者FOXP3基因在位點rs3761549表現G基因型者，有較高的機會發生食道共同癌，且有預後較差的趨勢，這類病人需要較積極的內視鏡篩檢以提早發現食道共同癌。

Background: Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignant disease worldwide. It is commonly associated with synchronous esophageal squamous cell carcinoma (SCC) due to similar carcinogens exposure, such as cigarette smoking and alcohol drinking. When the two cancers developed simultaneously, so called synchronous SCC, the outcome is extremely poorer than either one alone. Therefore, it is important to diagnose synchronous SCC in the early stages. In addition to the documented risk factors such as smoking, drinking and hypopharyngeal location of head and neck cancer, recent study showed aberrant regulatory T cell (Treg) infiltration may contribute to the development of synchronous SCC of upper aerodigestive tract. FOXP3 is a master regulator of Treg development and function. We aimed to investigate whether genetic polymorphism in FOXP3 is associated with aberrant Treg infiltration, risk of synchronous SCC and patient survival in HNSCC patients.
Methods: We consecutively enrolled HNSCC patients who received screening esophagogastroduodenoscopy from 2009 to 2016 in National Cheng Kung University Hospital and E-DA Hospital. Three tag single nucleotide polymorphisms (rs2232365, rs3761548 and rs3761549) were selected from Hapmap database of Chinese Han group. Patients’ DNA was extracted from peripheral lymphocyte and genotyped by real-time PCR. Treg infiltration in tumor tissue was evaluated by immunohistochemistry. The association between FOXP3 genotypes and synchronous SCC risk, patient prognosis and Treg infiltration were analyzed.
Result: A Total of 270 patients with matched gender (male only, because female was extremely rare), smoking and alcohol usage state were included for final analyses (135 with HNSCC alone and 135 with synchronous SCC). We confirmed that hypopharyngeal location of HNSCC significantly correlated to synchronous SCC development (p = 0.012, OR = 1.87). In the 3 selected tag-SNPs, rs3761549 G allele was significantly associated with increased synchronous SCC risk (OR = 2.205, 95%CI 1.215-4.002, p = 0.009). After adjusting HNSCC location and HNSCC tumor stage, rs3761549 G allele was an independent risk factor for synchronous SCC (aOR=2.10, 95% CI 1.105-4.002, p = 0.024). There was highly linkage between the 3 tag-SNPs and Haplotype C-G-A (rs2232365/3761548/3761549) also significantly protected from synchronous SCC development (OR=0.453, 95% CI 0.250-0.823, p = 0.009). In addition, patient with G allele in rs3761549 had significantly higher FOXP3+ Treg infiltration in the tumor tissue (mean FOXP3+ cell number/mm2 55.93 vs. 36.39, p = 0.008). Patients carrying G allele in rs3761549 also had a trend of poorer overall survival in the subgroup of late-stage HNSCC (G allele vs. A allele 41.5 +/- 3.6 months vs 46.6 +/- 5.1 months).
Conclusion: Male HNSCC patients who carries G allele in rs3761549 of the FOXP3 gene has a higher risk for synchronous SCC development and trend of poorer outcome. They warrant intensive EGD checkup to diagnose synchronous cancer as early

摘要 i
Abstract iv
Acknowledgement vii
Table of Contents viii
Abbreviation x
Chapter 1: Introduction 1
1.1 Cancer of upper aerodigestive tract 1
1.2 Synchronous second primary malignancy 3
1.3 Regulatory T cell (Treg): function and regulation 5
1.4 Single nucleotide polymorphism (SNP) 8
1.5 Dissertation aims 9
Chapter 2: Materials and methods 10
2.1 Patient enrollment 10
2.2 Tag single nucleotide polymorphism selection 11
2.3 DNA extraction and genotyping 12
2.4 FOXP3+ Treg density in tumor tissue by Immunohistochemistry 12
2.5 Statistic analyses 13
Chapter 3: Result 15
3.1 Baseline characteristics of enrolled patients 15
3.2 The association between FOXP3 genotypes and synchronous SCC risk 15
3.3 Abundance of FOXP3+ regulatory T cell infiltration in tumor tissue of patients carrying risk genotype 17
3.4 The association between FOXP3 genotype and survival of UADT SCC patients 18
Chapter 4: Discussion 19
Chapter 5 Conclusion 24
Tables and Figures 25
Table 1. The allele frequencies of the 3 selected FOXP3 tag-SNPs in Chinese Han Beijing (CHB) group from Hapmap database 25
Table 2. Baseline characteristics of the enrolled patients 26
Table 3. The association between FOXP3 genotypes and synchronous SCC risk 27
Table 4. The association between FOXP3 haplotypes and SynSCC risk 28
Table 5. Summary of recent studies discussing about FOXP3 polymorphism and cancer risk 29
Figure 1. Schematic of Treg suppression mechanism. 30
Figure 2. Schematic of patient enrollment process in this study. 31
Figure 3. LD plots of FOXP3 gene SNPs 32
Figure 4. Representative pictures of FOXP3+ Treg infiltration in the tumor tissues of patients with different FOXP3 genotypes. 33
Figure 5. Foxp3+ Treg densities in the tumor tissues of patients with different FOXP3 genotypes. 35
Figure 6. Comparison of overall survival by disease phenotype and FOXP3 genotype. 36
Figure 7. The survival curve of head and neck cancer patients based on FOXP3 genotype. 38
Figure 8. The survival curve of synchronous SCC patients based on FOXP3 genotype 40
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