Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component

Masaki Suzuki; Rika Kasajima; Tomoyuki Yokose; Hiroyuki Ito; Eigo Shimizu; Seira Hatakeyama; Kazuaki Yokoyama; Rui Yamaguchi; Yoichi Furukawa; Satoru Miyano; Seiya Imoto; Emi Yoshioka; Kota Washimi; Yoichiro Okubo; Kae Kawachi; Shinya Sato; Yohei Miyagi

doi:10.21037/tlcr-20-1158

Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component

Transl Lung Cancer Res. 2021 Mar;10(3):1292-1304. doi: 10.21037/tlcr-20-1158.

Authors

Masaki Suzuki¹, Rika Kasajima^{2

3}, Tomoyuki Yokose¹, Hiroyuki Ito⁴, Eigo Shimizu³, Seira Hatakeyama⁵, Kazuaki Yokoyama⁶, Rui Yamaguchi^{3

7

8}, Yoichi Furukawa⁵, Satoru Miyano^{3

9}, Seiya Imoto³, Emi Yoshioka¹, Kota Washimi¹, Yoichiro Okubo¹, Kae Kawachi¹, Shinya Sato², Yohei Miyagi²

Affiliations

¹ Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.
² Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
³ Division of Health Medical Intelligence, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴ Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan.
⁵ Division of Clinical Genome Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶ Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁷ Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁸ Division of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹ Department of Integrated Data Science, Medical and Dental Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Background: Fetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs.

Methods: We performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component.

Results: Cancer-related mutations were identified in TP53 (7/16 cases), KMT2C (6/16 cases), KRAS (4/16 cases), NF1 (3/16 cases), STK11 (3/16 cases), CTNNB1 (2/16 cases), and EGFR (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes NKX2-1 and SFTPC. H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells).

Conclusions: This study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of KMT2C mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.

Keywords: CTNNB1; High-grade fetal adenocarcinoma; KMT2C; programmed death ligand-1 (PD-L1); whole-exome sequencing (WES).