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Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression


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Two new studies released July 9th, 2020 in Cell unravel the biology of lung adenocarcinoma (LUAD) using a suite of molecular techniques that, combined, provide a more complete picture of the disease than ever before. Using a diverse cohort of smokers and non-smokers, male and female, from around the world, researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the International Cancer Proteogenome Consortium (ICPC) draw out a clearer understanding of LUAD tumor progression, identify biomarkers, and propose alternative therapeutic targets.

Lung cancer is the most commonly diagnosed cancer worldwide and the leading cause (link is external) of cancer-related deaths in both men and women in the United States. Despite the advent of improved drug therapies, the 5-year survival rate still remains below 20% because symptoms rarely show up until the cancer has spread to other parts of the body, making it extremely difficult to treat.

Advances in genomics have revealed new insights in the biology of LUAD, but comprehensive information about how various gene mutations lead to this disease is still lacking. CPTAC and ICPC investigators addressed this challenge by adding comprehensive proteomics to genomics, or proteogenomics, to reveal an additional dimension of lung cancer biology.

Molecular Signatures of Pathogenesis and Progression in East Asia

Although strongly associated with smoking, significant populations of never-smokers also develop lung cancer. While never-smokers account for approximately 20%(link is external) of lung cancer patients in the United States, in Taiwan more than 50% of patients are never-smokers, and many with early onset of the disease. The high number of East Asian LUAD never-smokers presented an opportunity for the ICPC-Taiwan team, led by Drs. Yu-Ju Chen and Pan-Chyr Yang with colleagues from Academia Sinica(link is external), National Taiwan University(link is external), Taipei Medical University(link is external), Taiwan and The Institute of Cancer Research(link is external), UK, to take a closer look(link is external) at the mechanisms of this disease in 103 East Asian patients with a focus on early stage.

Comparison of tumor/normal matched tissue pairs revealed strong associations between APOBEC mutagenesis and carcinogenesis. The APOBEC family of RNA-editing enzymes function to make specific changes to transcripts and allow a single protein to operate differently in different organs. In 74% of the younger female never-smokers (<60 years old) and all female patients without EGFR driver mutations in this study, researchers found high APOBEC mutational signatures, accompanied by high expression of APOBEC family enzymes and DNA repair/replication pathways upon combining proteomic and phosphoproteomic profiles. In addition, a correlation between high APOBEC signature and good response to immunotherapy was observed, making it a potential marker candidate for early stage diagnosis and immunotherapy treatment. However, in older females (>70 years old), mutagenesis derived from exposure of environmental carcinogens were found to be the prominent cancer drivers at early stages. Furthermore, proteomics showed additional evidences in the activated signaling in the metabolism and detoxification of chemical carcinogens, and pathways potentially causing tumor initiation, malignant progression and immune modulation in early carcinogenesis, suggesting that reducing carcinogen exposure from air pollutants and food preservatives maybe an effective strategy to improve lung cancer prevention.

Furthermore, proteomic characterization of the cohort stratified patients into five distinct subtypes, revealing a novel ‘late-like’ subtype (Stage 1B ‘late-like’) in patients with EGFR L858R mutations that display aggressive clinical features. Taiwanese patients have previously been shown to have a demographically distinct cancer genome mainly driven by two EGFR mutations: Del19 and L858R, the latter being associated with shorter survival outcomes and higher tendencies to develop malignant pleural effusion and metastasis without a clear mechanism. This study shows a molecular distinction between tumors with EGFR Del19 and L858R genetic mutations. These new findings suggest an early point of divergence in tumor phenotype where clinicians could identify high-risk patients to receive closer monitoring and possible adjuvant therapy. Early stage ‘late-like’ tumors also showed significant increases in MMP11, an enzyme that cuts away at the surrounding tissue, that may also serve as a strong early stage biomarker candidate.

“Proteogenomics helped identify demographically distinct signatures of oncogenesis and progression in never-smokers,” Dr. Yang said. “This approach has provided new insights on the management of early stage never-smokers with LUAD.”

Both these studies, CPTAC and ICPC, layer comprehensive multi-omic analysis to uncover findings that would otherwise remain disconnected. The discovery of new lung tumor biology and a continuous look at early stage LUAD development provides a significant boost to help develop strategies for detection and management.

“The collective findings of these studies are a result of using proteogenomics in research to produce an additional dimension to cancer biology and organizations working together to take on cancer, with a focus on patients as cancer knows no borders,” said Dr. Henry Rodriguez, Director of NCI’s Office of Cancer Clinical Proteomics Research.

These studies are a part of a series of studies supported by the National Cancer Institute’s (NCI’s) CPTAC and ICPC programs to fight cancer using proteogenomics and precision oncology. Previously published papers from these programs have focused on endometrial, kidney, breast, ovarian and colon cancers. Both studies have produced proteogenomic datasets that are available as a unique public resource for researchers and clinicians seeking to better understand and treat lung cancer.

Media Contact:
Dr. Yu-Ju Chen, Distinguished Research Fellow/ Acting Director, Institute of Chemistry, Academia Sinica
(Tel) +886-2-5572-8660,
Mr. Chung-Hui Chuang, Secretariat Office, Central Office of Administration, Academia Sinica
(Tel) +886-2-2789-8820,
Mr. Chang-Hung Chen, Secretariat Office, Central Office of Administration, Academia Sinica
(Tel) +886-2-2789-8059,



肺癌致病的關鍵: APOBEC 突變特徵、致癌物效應










本院擁有領先世界的蛋白基因體技術、生物資訊分析平台與大數據分析技術,且臺灣醫療團隊具備完善的長期追蹤資料。藉此優勢,本院與美國國家癌症研究所(National Cancer Institute, NCI)於2016年簽署「癌症登月計畫(Cancer Moonshot)」合作備忘錄,參與國際癌症蛋白基因體學聯盟(International Cancer Proteogenome Consortium, ICPC)。同年10月臺灣通過生醫產業推動方案,科技會報將癌症登月計畫納入為「推動特色重點產業」策略之一,提供利用蛋白基因體大數據開發創新診斷及新藥研發之契機。


論文共同第一作者為本院化學所陳誼如博士後、本院統計所張雅媗博士後及英國癌症研究所 Theodoros I. Roumeliotis,本院資訊所陳鯨太博士後及時任本院化學所林妙霞博士後 (現任臺灣大學)亦列為共同第二作者。研究團隊包括本院化學所陳玉如所長、本院楊泮池院士、本院統計所陳璿宇副研究員、英國癌症研究所Jyoti S. Choudhary、臺灣大學醫學檢驗暨生物技術學系與基因體暨精準醫學研究中心俞松良教授、臺大醫院外科醫師陳晉興、本院資訊科學研究所宋定懿研究員及臺北醫學大學韓嘉莉助理教授等。本次研究經費主要來自科技部、中研院及臺灣大學支持。

論文全文連結:〈Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression〉。網址:

(Tel) 02-5572-8660,yujuchen@
(Tel) 02-2789-8820,
(Tel) 02-2789-8059,