Dataset Information

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

ABSTRACT: Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

SUBMITTER: Chen H

PROVIDER: S-EPMC6884501 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genomic and immune profiling of pre-invasive lung adenocarcinoma.

Chen Haiquan H Carrot-Zhang Jian J Zhao Yue Y Hu Haichuan H Freeman Samuel S SS Yu Su S Ha Gavin G Taylor Alison M AM Berger Ashton C AC Westlake Lindsay L Zheng Yuanting Y Zhang Jiyang J Ramachandran Aruna A Zheng Qiang Q Pan Yunjian Y Zheng Difan D Zheng Shanbo S Cheng Chao C Kuang Muyu M Zhou Xiaoyan X Zhang Yang Y Li Hang H Ye Ting T Ma Yuan Y Gao Zhendong Z Tao Xiaoting X Han Han H Shang Jun J Yu Ying Y Bao Ding D Huang Yechao Y Li Xiangnan X Zhang Yawei Y Xiang Jiaqing J Sun Yihua Y Li Yuan Y Cherniack Andrew D AD Campbell Joshua D JD Shi Leming L Meyerson Matthew M

Nature communications 20191129 1

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in fr ...[more]

PMID: 31784532

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Project description:BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.

Project description:ImportanceSmall-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking.ObjectiveTo perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations.Design, setting, and participantsProspective analysis was performed of clinical samples from patients with SBA (n?=?317), colorectal cancer (n?=?6353), and gastric carcinoma (n?=?889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions.ResultsOf the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P?<?.001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P?<?.001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P?<?.001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P?<?.001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P?<?.001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease-associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series.Conclusions and relevanceThis study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy.

Dataset Information

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

Publications

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

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