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Nishioka et al. Hepatoma Research 2018;4:1 Hepatoma Research
DOI: 10.20517/2394-5079.2017.46

Original Article Open Access

Clinical and molecular sub-classification of
hepatocellular carcinoma relative to alpha-
fetoprotein level in an Asia-Pacific island cohort

Scott T. Nishioka , Miles M. Sato , Linda L. Wong , Maarit Tiirikainen , Sandi A. Kwee 1,2,3
1
1
2
2
1 The Queen’s Medical Center, Honolulu, HI 96813, USA.
2 Cancer Biology Program and Genomics Shared Resource, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI
96822, USA.
3 Hamamatsu/Queen's PET Imaging Center, The Queen’s Medical Center, Honolulu, HI 96813, USA.
Correspondence to: Dr. Sandi A. Kwee, The Queen’s Medical Center, Honolulu, HI 96813, USA. E-mail: kwee@hawaii.edu
How to cite this article: Nishioka ST, Sato MM, Wong LL, Tiirikainen M, Kwee SA. Clinical and molecular sub-classification of
hepatocellular carcinoma relative to alpha-fetoprotein level in an Asia-Pacific island cohor. Hepatoma Res 2018;4:1.
http://dx.doi.org/10.20517/2394-5079.2017.46

Received: 20 Oct 2017 First Decision: 21 Nov 2017 Revised: 5 Dec 2017 Accepted: 5 Dec 2017 Published: 12 Jan 2018
Science Editor: Guang-Wen Cao Copy Editor: Lu Liu Production Editor: Huan-Liang Wu

Abstract
Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular sub-classes of
hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment
of this disease. Considering recent efforts to validate HCC molecular classification systems across different
populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether
associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be
found in Hawaii, a region with a unique demographic and risk factor profile for HCC.

Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients
following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-
classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with
regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were
also examined at the gene signature level by gene set enrichment analysis.

Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of
tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels
in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted
significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical
prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant
predictors of overall survival.

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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