BACKGROUND & AIMS: Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk. METHODS: We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, eHCC (n = 5) and pHCC (n = 3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis. RESULTS: We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGFβ, WNT, NOTCH, and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC. CONCLUSIONS: Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses.
BACKGROUND & AIMS:Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk. METHODS: We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, eHCC (n = 5) and pHCC (n = 3) from 8 HCCpatients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis. RESULTS: We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGFβ, WNT, NOTCH, and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC. CONCLUSIONS: Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses.
Authors: Leilei Chen; Yan Li; Chi Ho Lin; Tim Hon Man Chan; Raymond Kwok Kei Chow; Yangyang Song; Ming Liu; Yun-Fei Yuan; Li Fu; Kar Lok Kong; Lihua Qi; Yan Li; Na Zhang; Amy Hin Yan Tong; Dora Lai-Wan Kwong; Kwan Man; Chung Mau Lo; Si Lok; Daniel G Tenen; Xin-Yuan Guan Journal: Nat Med Date: 2013-01-06 Impact factor: 53.440
Authors: Carl F Schaefer; Kira Anthony; Shiva Krupa; Jeffrey Buchoff; Matthew Day; Timo Hannay; Kenneth H Buetow Journal: Nucleic Acids Res Date: 2008-10-02 Impact factor: 16.971
Authors: Yichen Xu; Mauro Poggio; Hyun Yong Jin; Zhen Shi; Craig M Forester; Ying Wang; Craig R Stumpf; Lingru Xue; Emily Devericks; Lomon So; Hao G Nguyen; Alice Griselin; John D Gordan; Sarah E Umetsu; Siegfried H Reich; Stephen T Worland; Saurabh Asthana; Maria Barna; Kevin R Webster; John T Cunningham; Davide Ruggero Journal: Nat Med Date: 2019-01-14 Impact factor: 53.440
Authors: Ryan A Hlady; Dan Zhou; William Puszyk; Lewis R Roberts; Chen Liu; Keith D Robertson Journal: Epigenetics Date: 2017-01-06 Impact factor: 4.528
Authors: Avrum Spira; Matthew B Yurgelun; Ludmil Alexandrov; Anjana Rao; Rafael Bejar; Kornelia Polyak; Marios Giannakis; Ali Shilatifard; Olivera J Finn; Madhav Dhodapkar; Neil E Kay; Esteban Braggio; Eduardo Vilar; Sarah A Mazzilli; Timothy R Rebbeck; Judy E Garber; Victor E Velculescu; Mary L Disis; Douglas C Wallace; Scott M Lippman Journal: Cancer Res Date: 2017-04-01 Impact factor: 13.312