Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component

Shirong Zhang; Yang Xu; Pan Zhao; Hua Bao; Xiyong Wang; Rui Liu; Rujun Xu; Jingjing Xiang; Hong Jiang; Junrong Yan; Xue Wu; Yang Shao; Jiafeng Liang; Qiong Wu; Zhihao Zhang; Shun Lu; Shenglin Ma

doi:10.3389/fonc.2021.652193

Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component

Front Oncol. 2021 Jun 17:11:652193. doi: 10.3389/fonc.2021.652193. eCollection 2021.

Authors

Shirong Zhang¹, Yang Xu², Pan Zhao³, Hua Bao², Xiyong Wang⁴, Rui Liu², Rujun Xu³, Jingjing Xiang³, Hong Jiang⁵, Junrong Yan², Xue Wu², Yang Shao^{2

6}, Jiafeng Liang¹, Qiong Wu¹, Zhihao Zhang⁴, Shun Lu⁷, Shenglin Ma¹

Affiliations

¹ Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China.
² Research and Development, Nanjing Geneseeq Technology Inc., Nanjing, China.
³ Department of Pathology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Thoracic Surgery, Hospital of Marine Police Corps, Jiaxing, China.
⁵ Department of Thoracic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ School of Public Health, Nanjing Medical University, Nanjing, China.
⁷ Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.

Methods: We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.

Results: Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.

Conclusion: We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.

Keywords: brain-specific angiogenesis inhibitor 3; immunotherapy; micropapillary adenocarcinoma; transcription termination factor 1; tumor mutation burden.