The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.

Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study

“…We cannot discount the possibility that biologic factors intrinsic to the molecular makeup of HCC might be at the basis of the different survival periods observed between the PT and the TN group, more so in light of recent evidence suggesting genomic diversity in the evolution of HCC [34]. It is possible that in the PT group, the HCC might have had a more indolent course that allowed early detection and facilitated the provision of multiple lines of treatment, leading to better patient selection.…”

The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

“…6D), where the JAK1 mutation was validated as an oncogenic driver in a previous study. (13) To uncover the driver genes affected by AA, (25) we further investigated the human liver cancers that (8) Kan et al (13) China (Hong Kong) 88 7 (8) 4 (5) 1 (1) Lin et al (14) China (mainland) 11 6 (55) 5 (45) 1 (9) Ng et al (9) Taiwan 98 68 (69) 63 (64) 47 (48) Chinese HCC total 510 133 (26) 107 (21) 75 (15) TCGA (20) USA (Asian) 160 24 (15) 18 (11) 10 (5) TCGA (20) USA (others) 204 5 (2) 4 (2) 1 (<1) ICGC (19) France 249 1 (<1) 0 (0) 0 (0) ICGC (17,18) Japan 594 3 (<1) 1 (<1) 0 (0)…”

“…Zhai et al (15) Singapore 9 4 (44) 2 (22) 1 (11) Ahn et al (16) Korea 231 16 (7) 12 (5) 8 (3) Worldwide HCC total 1,957 186 (10) 144 (7) 95 (5) ICC Zou et al (21) China (mainland) 103 11 (11) 8 (8) 3 (3) cHCC-ICC Xue et al (22) Asia ‡ 121 29 (24) 20 (17) 17 (14) *Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure > 0 (P < 0.05). † Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure no less than 20% (P < 0.05).…”

Vital Ex Vivo Tissue Labeling and Pathology-Guided Micropunching to Characterize Cellular Heterogeneity in the Tissue Microenvironment

“…This “microenviromental heterogeneity” can occur predictably when driven by tissue architecture, as is seen with periportal and perivascular hepatocytes that harbor extensive differences in drug metabolic activity in response to differences in oxygen tension. Alternatively, microenvironmental heterogeneity can present apparently at random, driven by unseen molecular changes as occurs with treatment resistant foci of a tumor (3,4). Microenvironmental heterogeneity underlies critical biology that is key to understanding human health and disease in many different contexts.…”