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Clinicopathological indices to predict hepatocellular carcinoma molecular classification
Author(s) -
Tan Poh Seng,
Nakagawa Shigeki,
Goossens Nicolas,
Venkatesh Anu,
Huang Tiangui,
Ward Stephen C.,
Sun Xiaochen,
Song WonMin,
Koh Anna,
CanastoChibuque Claudia,
Deshmukh Manjeet,
Nair Venugopalan,
Mahajan Milind,
Zhang Bin,
Fiel Maria Isabel,
Kobayashi Masahiro,
Kumada Hiromitsu,
Hoshida Yujin
Publication year - 2016
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12889
Subject(s) - subclass , hepatocellular carcinoma , medicine , carcinoma , oncogene , oncology , cancer , cancer research , pathology , immunology , antibody , cell cycle
Background & Aims Hepatocellular carcinoma ( HCC ) is the second most lethal cancer caused by lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti‐ HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. Methods Hepatocellular carcinoma classification defined in our previous transcriptome meta‐analysis (S1, S2 and S3 subclasses) was implemented in an FDA ‐approved diagnostic platform (Elements assay, NanoString). Ninety‐six HCC tumours (training set) were assayed to develop molecular subclass‐predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumours (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. Results Hepatocellular carcinoma subclass‐predictive indices were steatohepatitic ( SH )‐ HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha‐foetoprotein (>400 ng/ml) for S2 subclass, and microtrabecular pattern, lack of SH ‐ HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with the activation of therapeutically targetable oncogene YAP and stemness markers EPCAM / KRT 19 . BMP 4 was associated with pseudoglandular pattern. Subclass‐predictive indices‐based patient enrichment reduced clinical trial sample sizes from 121, 184 and 53 to 30, 43 and 22 for S1, S2 and S3 subclass‐targeting therapies respectively. Conclusions Hepatocellular carcinoma molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways.