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Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

ABSTRACT: Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.

SUBMITTER: Zhai W

PROVIDER: S-EPMC8973408 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

Zhai Weiwei W Lai Hannah H Kaya Neslihan Arife NA Chen Jianbin J Yang Hechuan H Lu Bingxin B Lim Jia Qi JQ Ma Siming S Chew Sin Chi SC Chua Khi Pin KP Alvarez Jacob Josiah Santiago JJS Chen Pauline Jieqi PJ Chang Mei Mei MM Wu Lingyan L Goh Brian K P BKP Chung Alexander Yaw-Fui AY Chan Chung Yip CY Cheow Peng Chung PC Lee Ser Yee SY Kam Juinn Huar JH Kow Alfred Wei-Chieh AW Ganpathi Iyer Shridhar IS Chanwat Rawisak R Thammasiri Jidapa J Yoong Boon Koon BK Ong Diana Bee-Lan DB de Villa Vanessa H VH Dela Cruz Rouchelle D RD Loh Tracy Jiezhen TJ Wan Wei Keat WK Zeng Zeng Z Skanderup Anders Jacobsen AJ Pang Yin Huei YH Madhavan Krishnakumar K Lim Tony Kiat-Hon TK Bonney Glenn G Leow Wei Qiang WQ Chew Valerie V Dan Yock Young YY Tam Wai Leong WL Toh Han Chong HC Foo Roger Sik-Yin RS Chow Pierce Kah-Hoe PK

National science review 20211029 3

Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH ...[more]

PMID: 35382356

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Project description:IntroductionMounting evidence has revealed that the interactions and dynamic alterations among immune cells are critical in shaping the tumor microenvironment and ultimately map onto heterogeneous clinical outcomes. Currently, the underlying clinical significance of immune cell evolutions remains largely unexplored in hepatocellular carcinoma (HCC).MethodsA total of 3,817 immune cells and 1,750 HCC patients of 15 independent public datasets were retrieved. The Seurat and Monocle algorithms were used to depict T cell evolution, and nonnegative matrix factorization (NMF) was further applied to identify the molecular classification. Subsequently, the prognosis, biological characteristics, genomic variations, and immune landscape among distinct clusters were decoded. The clinical efficacy of multiple treatment approaches was further investigated.ResultsAccording to trajectory gene expression, three heterogeneous clusters with different clinical outcomes were identified. C2, with a more advanced pathological stage, presented the most dismal prognosis relative to C1 and C3. Eight independent external cohorts validated the robustness and reproducibility of the three clusters. Further explorations elucidated C1 to be characterized as lipid metabolic HCC, and C2 was referred to as cell-proliferative HCC, whereas C3 was defined as immune inflammatory HCC. Moreover, C2 also displayed the most conspicuous genomic instability, and C3 was deemed as "immune-hot", having abundant immune cells and an elevated expression of immune checkpoints. The assessments of therapeutic intervention suggested that patients in C1 were suitable for transcatheter arterial chemoembolization treatment, and patients in C2 were sensitive to tyrosine kinase inhibitors, while patients in C3 were more responsive to immunotherapy. We also identified numerous underlying therapeutic agents, which might be conducive to clinical transformation in the future.ConclusionsOur study developed three clusters with distinct characteristics based on immune cell evolutions. For specifically stratified patients, we proposed individualized treatment strategies to improve the clinical outcomes and facilitate the clinical management.

Dataset Information

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

Publications

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

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