大腸直腸癌（CRC）是世界上第三大常見的癌症型別，也是台灣癌症相關死亡率的第三大原因。CRC腫瘤發生被稱為多步驟過程，並且通常從腫瘤抑制基因adenomatous polyposis coli (APC)的突變和/或喪失作為開始。雖然許多其他基因或染色體改變已被證明也參與這個過程，但仍然可能有未識別的分子參與在CRC腫瘤發生中。釐清 CRC腫瘤發生的分子機制可能有助於我們改善這種疾病的管理和治療。在本研究中，我們使用高密度array CGH (aCGH)來確定與CRC腫瘤發生顯著相關的最小染色體區域的拷貝數變異（CNA）。我們總共調查了377個無家族病史的CRC病例，實驗結果顯示最常見和最小染色體區域是20q13.33的拷貝數增加，以及20p12.1和4q22.1的拷貝數缺失。為了確認aCGH的結果, 我們使用CDH4, MACROD2,兩個基因SPP1和FAM190A代表染色體20q13.33, 20p12.1,和4q22.1利用定量qPCR。接著利用定量qPCR，數據顯示與aCGH結果一致。在20q13.33的拷貝數增加是顯著的改變(50.9%)。此外，我們發現20q13.33的拷貝數增加與年齡(50歲以上)、AJCC I期，微衛星穩定性（MSS）、及腫瘤的一些特徵作為位置和分化狀態的臨床病理特徵有顯著相關（p < 0.05）。為了確認20q13.33拷貝數增加在CRC腫瘤發生早期中的作用，我們調查了這項改變在160例共198結腸直腸息肉患者的發生率。我們發現62.6％的結腸直腸息肉有20q13.33拷貝數增加的現象。利用4對CRC的轉錄基因體次世代定序（RNA-seq）數據，我們鑑定了位於20q13.33的7個候選基因為SLC2A4RG，PSMA7，MRGBP，GID8，YTHDF1，PCMTD2和COL9A3。進一步利用生物資訊學工具Metacore和GeneMANIA，以及即時定量PCR的結果讓我們確定了三個候選基因，PSMA7，GID8和YTHDF1不但在CRC的表現量與拷貝數增加呈高度相關，在大腸瘜肉中也有表達。這些候選基因值得進一步調查與探討其高度表現對CRC腫瘤發生的影響。總結來說,我們的研究確定了20q13.33的拷貝數增加為大腸直腸癌腫瘤發生的早期事件. 此外,我們還提供了特定的基因變異模式以幫助區分大腸息肉的兩個主要亞型。最後我們也提出染色體20q13.33中的三個候選基因(PSMA7，GID8和YTHDF1) 可以是大腸直腸癌腫瘤發生的早期基因組生物標誌.

Colorectal carcinoma (CRC) is the third common cancer in the world and also the third major leading cause of cancer-related mortality in Taiwan. CRC tumorigenesis is known as a multistep process and typically starts from the mutation and / or loss of a tumor suppressor gene as adenomatous polyposis coli. Although many genes or chromosomal alterations have been shown to be involved in this process, there have been still unrecognized molecular events remained to be identified in CRC tumorigenesis. The clarification of CRC tumorigenesis may help us to improve the management and treatment of this disease. In this study, using the high-resolution array CGH (aCGH), we aimed to identify copy number alterations (CNAs) of the recurrent minimal chromosomal regions (MCRs) that are significantly associated with CRC tumorigenesis. A total of 377 CRC cases were investigated and revealed that the recurrent MCRs are gains in 20q13.33, losses in 20p12.1 and 4q22.1. To confirm aCGH results, we performed quantitative real-time PCR (qPCR) using CDH4, MACROD2, two genes SPP1 and FAM190A to represent chromosomes 20q13.33, 20p12.1 and 4q22.1, respectively. Our qPCR data showed agreements to aCGH results, then gain in 20q13.33 was the most significant common alteration (50.9%). Furthermore, we found that gain in 20q13.33 was significantly correlated to clinicopathological features as age over 50, AJCC stage I / II, microsatellite stable (MSS), left-sided and moderately differentiated tumors (p < 0.05). To confirm the role of 20q13.33 gain in CRC tumorigenesis, we investigated this alteration in 160 patients with 198 colon polyps. We found that the frequency of 20q13.33 gain was 62.6% of colon polyps. Based on RNA-sequencing data of 4 sporadic CRCs, we identified 7 candidate genes located at 20q13.33 as SLC2A4RG, PSMA7, MRGBP, GID8, YTHDF1, PCMTD2 and COL9A3. Applying some bioinformatics tools as Metacore and GeneMANIA, as well as performing quantitative real-time PCR, we identified three candidate genes (PSMA7, GID8, and YTHDF1), which are highly expressed at the early stages of CRC and in correlation to copy number gain of CRC patients. Further investigation on these three candidates should explore their roles as the early genomic biomarkers for CRC tumorigenesis. In conclusion, our study firstly identified 20q13.33 copy number gain as an early event in CRC tumorigenesis. Moreover, we also provided specific mutation profiles to help to distinguish two main subtypes of colon polyps, such as adenomatous and serrated polyps. Particularly, three candidates (PSMA7, GID8, and YTHDF1) located in chromosome 20q13.33 can be the promising candidates as well as early genomic biomarkers for CRC tumorigenesis.

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