A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory.
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Chen Jianbin, Kaya Neslihan Arife, Zhang Ying, Kendarsari Raden Indah, Sekar Karthik, Lee Chong Shay, Seshachalam Veerabrahma Pratap, Ling Wen Huan, Jin Phua Cheryl Zi, Lai Hannah, Yang Hechuan, Lu Bingxin, Lim Jia Qi, Ma Siming, Chew Sin Chi, Chua Khi Pin, Santiago Alvarez Jacob Josiah, Wu Lingyan, Ooi London, Yaw-Fui Chung Alexander, Cheow Peng Chung, Kam Juinn Huar, Wei-Chieh Kow Alfred, Ganpathi Iyer Shridhar, Bunchaliew Chairat, Thammasiri Jidapa, Koh Peng Soon, Bee-Lan Ong Diana, Lim Jasmine, de Villa Vanessa H, Dela Cruz Rouchelle D, Loh Tracy Jiezhen, Wan Wei Keat, Leow Wei Qiang, Yang Yi, Liu Jin, Skanderup Anders Jacobsen, Pang Yin Huei, Ting Soon Gwyneth Shook, Madhavan Krishnakumar, Kiat-Hon Lim Tony, Bonney Glenn, Goh Brian K P, Chew Valerie, Dan Yock Young, Toh Han Chong, Sik-Yin Foo Roger, Tam Wai Leong, Zhai Weiwei, Kah-Hoe Chow Pierce
Аннотация
METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients.
RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival.
CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories.
IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making.
CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).