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Genomic origin and intratumor heterogeneity revealed by sequencing on carcinomatous and sarcomatous components of pulmonary sarcomatoid carcinoma

Abstract

Pulmonary sarcomatoid carcinoma (PSC) contains carcinomatous component (CaC) and sarcomatous component (SaC). Herein, we explored the genomic origin and intratumor heterogeneity (ITH) of PSC. We collected 31 resected PSC tumors and obtained CaC and SaC by laser capture microdissection for next-generation sequencing. The majority of PSCs (97%) had component-shared alterations. Driver mutations in EGFR, KRAS, MET, PIK3CA, and EML4-ALK fusion were mostly component-shared. Twenty-seven (87%) PSCs had component-private alterations. Compared with pure lung adenocarcinoma (LUAD), adenocarcinoma component of PSC showed lower EGFR incidence. Compared with other typical sarcomas, numerous genes of SaC exhibited significant differences. CaC and SaC had equivalent and proportional tumor mutation burden (TMB), as well as PD-L1 level. Compared with LUAD, SaC had significant higher TMB and more patients with high PD-L1 expression (tumor proportion score ≥50%). PSC with lower proportion of component-shared alterations (trunk-ratio) had a prolonged disease-free survival (DFS), regardless of the influence of clinical factors. We conclude that most PSCs originate from a monoclone accompanied by genomic ITH which is a potential independent prognostic factor, and more proportion of PSCs may be beneficial from immune checkpoint inhibitors.

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Fig. 1: Genomic landscape of PSC.
Fig. 2: Genetic origin and branch evolution of PSC.
Fig. 3: Genomic comparison between PSCs and LUADs and sarcomas.
Fig. 4: TMB value and PD-L1 expression in PSC.
Fig. 5: Association of clinical or molecular features and clinical outcome.

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Data availability

The datasets supporting the conclusions of this article are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81572270), Nature Science Foundation of Hunan Province (2017JJ3188), Foundation of Hunan Health Committee Research Plan (A2017005) and Foundation of Wisdom Gathering and Talent Cultivating Program from the Third Xiangya Hospital.

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Authors

Contributions

L Chen and CM conceived the study and designed the experiments. XL, FW, XC, XH, ZX, and YL prepared the research materials. QL, PL, and L Chang did the bioinformatic analysis and performed initial exploratory analysis. YG, XZ, LY, CX, HW, XY, JZ, and XX provided insight in methodological approaches and analysis. XL and L Chen supervised the study. XL, FW, CX, XC, XH, QL, and PL drafted the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cesar Moran or Likun Chen.

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Conflict of interest

The authors declare the following conflict of interest: QL, PL, L Chang, YG, and XX are current employees of Geneplus-Beijing. XY and LY hold leadership positions and stocks of Geneplus-Beijing. JZ reports grants from Merck, Johnson and Johnson, consultant fees, advisory fees or honoraria from Bristol Myers Squibb, AstraZeneca, Geneplus, Innovent, OrigMed, Roche outside the submitted work. The remaining authors declare no conflict of interest.

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The present study was reviewed and approved by the Research Ethics Committee of the Sun Yat-sen University Cancer Center (B2020-139-01).

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Liu, X., Wang, F., Xu, C. et al. Genomic origin and intratumor heterogeneity revealed by sequencing on carcinomatous and sarcomatous components of pulmonary sarcomatoid carcinoma. Oncogene 40, 821–832 (2021). https://doi.org/10.1038/s41388-020-01573-9

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