Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma

Yansong Huo; Leina Sun; Jie Yuan; Hua Zhang; Zhenfa Zhang; Lianmin Zhang; Wuhao Huang; Xiaoyan Sun; Zhe Tang; Yingnan Feng; Huilan Mo; Zuoquan Yang; Chao Zhang; Zicheng Yu; Dongsheng Yue; Bin Zhang; Changli Wang

doi:10.3389/fonc.2022.931209

Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma

Front Oncol. 2022 Aug 3:12:931209. doi: 10.3389/fonc.2022.931209. eCollection 2022.

Authors

Yansong Huo¹, Leina Sun², Jie Yuan³, Hua Zhang¹, Zhenfa Zhang¹, Lianmin Zhang¹, Wuhao Huang¹, Xiaoyan Sun¹, Zhe Tang¹, Yingnan Feng¹, Huilan Mo¹, Zuoquan Yang³, Chao Zhang³, Zicheng Yu³, Dongsheng Yue¹, Bin Zhang¹, Changli Wang¹

Affiliations

¹ Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
² Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
³ GenePlus-Shenzhen, Shenzhen, China.

Abstract

Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its malignant behaviors are substantially unknown. In this study, eight FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. More comprehensive analyses involving our samples and public validation cohorts on the two subtypes were performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited the largest disease-free survival (DFS) differences in our patients. EGFR was found with the highest mutation frequency. Additionally, shared mutations were observed between paired LEP and MIP components from single patients, and recurrent mutations were verified in the Lung-Broad, Lung-OncoSG, and TCGA-LUAD cohorts. Distinct biological processes or pathways were involved in the evolution of the two components. Besides, analyses of copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level, ITH, and the pervasive DNA damage response and WNT pathway gene alternations in the MIP component. Phylogenetic analysis of five pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses combining our samples and public cohorts, PTP4A3, NAPRT, and RECQL4 were identified to be co-amplified. Multi-omics data also demonstrated the immunosuppression prevalence in the MIP component. Our results uncovered the evolutionary pattern of the concomitant LEP and MIP components from the same patient that they were derived from the same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. We also confirmed the immunosuppression prevalence in the MIP subtype by multi-omics data analyses, which may have resulted in its unfavorable prognosis.

Keywords: copy number alternation; histological subtypes; intratumor heterogeneity; lung adenocarcinoma; whole-exome sequencing.