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      Characteristics of genomic alterations of lung adenocarcinoma in young never‐smokers

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          Abstract

          Non‐small‐cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never‐smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never‐smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never‐smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well‐known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer‐associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer‐related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer‐related structural variations (e.g., EML4‐ALK and KIF5B‐RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK ( SMG6‐ALK) and RET ( JMJD1C‐RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never‐smoker patients with LUAD when compared with the in‐house noncancer database ( p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never‐smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.

          Abstract

          What's new?

          Young patients with non‐small‐cell lung cancer (NSCLC) represent a distinct disease entity: they are often female, never smoked and usually present with lung adenoma carcinomas. Here the authors performed whole‐genome sequencing in patients with early‐onset NSCLC who never smoked and find an overall lower mutation burden and fewer classic driver substitutions. However, oncogenic fusions were found more frequently, underscoring that a unique molecular make‐up defines this specific subgroup of cancer patients.

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          Most cited references25

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          Genomic alterations in lung adenocarcinoma.

          Treatment for non-small-cell lung cancer is evolving from the use of cytotoxic chemotherapy to personalised treatment based on molecular alterations. This past decade has witnessed substantial progress in the treatment of patients with EGFR mutations and ALK rearrangements, and it is now possible to study complex genomic alterations in cancer using next-generation sequencing. Sequencing data from large-scale consortia, such as The Cancer Genome Atlas, as well as several independent groups, have helped identify novel drivers and potentially targetable alterations in lung adenocarcinomas. These data clearly suggest that lung adenocarcinoma is associated with distinct genomic alterations compared with other lung cancer subtypes, and highlight the widespread molecular heterogeneity that underlies the disease. In this Review, we discuss some of the key findings from genomic studies of lung adenocarcinoma.
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            Cancer incidence and mortality among young adults aged 20–39 years worldwide in 2012: a population-based study

            To date, the burden of cancer among young adults has rarely been studied in depth. Our aim was to describe the scale and profile of cancer incidence and mortality worldwide among 20-39 year-olds, highlighting major patterns by age, sex, development level, and geographical region.
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              Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non-Small-Cell Lung Cancer.

              Non-small-cell lung cancer (NSCLC) diagnosed in young patients is rare, and the genomics and clinical characteristics of this disease are poorly understood. In contrast, the diagnosis of other cancers at a young age has been demonstrated to define unique disease biology. Herein, we report on the association of young age with targetable genomic alterations and prognosis in a cohort of 2237 patients with NSCLC.
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                Author and article information

                Contributors
                weimin003@163.com
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley and Sons Inc. (Hoboken )
                0020-7136
                1097-0215
                07 May 2018
                01 October 2018
                : 143
                : 7 ( doiID: 10.1002/ijc.v143.7 )
                : 1696-1705
                Affiliations
                [ 1 ] Department of Respiratory and Critical Care Medicine West China Hospital, Sichuan University Chengdu Sichuan China
                [ 2 ] The Scientific and Technical Department Novogene Bioinformatics Institute Beijing China
                [ 3 ] State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy West China Hospital, Sichuan University Chengdu Sichuan China
                [ 4 ] Lab of Pathology, West China Hospital, Sichuan University Chengdu Sichuan China
                [ 5 ] Department of Pathology West China Hospital, Sichuan University Chengdu Sichuan China
                [ 6 ] Department of Thoracic Surgery West China Hospital, Sichuan University Chengdu Sichuan China
                Author notes
                [*] [* ] Correspondence to: Weimin Li, MD, PhD, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan 610041, China, Tel.: +86‐28‐8542‐3998, Fax: +86‐28‐8558‐2944, E‐mail: weimin003@ 123456163.com
                [†]

                W.L., P.T. and Y.W. are the joint first authors.

                Author information
                http://orcid.org/0000-0003-0985-0311
                Article
                IJC31542
                10.1002/ijc.31542
                6175072
                29667179
                1e689166-583d-4c9f-b32d-0eb225aaaca5
                © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 03 February 2018
                : 24 March 2018
                : 06 April 2018
                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 6210
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81372504
                Funded by: Science and Technology Support Program of Science and Technology Department of Sichuan Province
                Award ID: 2016CZYD0001
                Award ID: 2016SZ0073
                Categories
                Cancer Genetics and Epigenetics
                Cancer Genetics and Epigenetics
                Custom metadata
                2.0
                ijc31542
                1 October 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:08.10.2018

                Oncology & Radiotherapy
                lung adenocarcinoma,young age,genomics,genetic predisposition,next generation sequencing

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