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INTRODUCTION (NHGRI) to characterize the genomic data of more
than 30 different types of cancers, and accelerate
MicroRNAs (miRNA) are important biological understanding of the molecular basis of cancer.
regulators and play a critical role in controlling protein- Currently, there are 366 cancer patients in the cancer
coding genes’ expression at the post-transcriptional type of liver hepatocellular carcinoma, who provided
level. It is estimated that one third of human genes demographic, etiologic and clinical data, as well as
are directly or indirectly governed by miRNAs and tissue samples for TCGA study. The miRNA expression
they impact multiple cellular pathways involved in and corresponding etiologies and clinical data were
tumorigenesis. [1,2] Anomalous expression of miRNAs downloaded (up to June 16, 2015) from TCGA data
have been implicated in a wide variety of cancers, portal (https://tcga-data.nci.nih.gov/tcga/tcgaHome2.
including hepatocellular carcinoma (HCC), one of the jsp), and a total of 414 samples from 366 histologically
most common cancers and the third leading cause of confirmed liver cancer patients have completed miRNAs,
cancer death worldwide. The incidence of HCC has etiologic and clinical data. After checking histologic
tripled over the past 30 years in the United States, [3,4] diagnosis and tissue types, we excluded 10 non-HCC
which may be attributed to increased hepatitis C virus cases (either mixed hepatocholangiocarcinoma or
(HCV) infection and obesity-related nonalcoholic fatty fibrolamellar carcinoma); 5 recurrent HCC tumors and
liver disease (NAFLD). [4,5] Other established etiologies 1 HCC non-tumor tissue without relevant paired tumor
of HCC are hepatitis B virus (HBV) infection, alcohol tissue. Finally, data from 48 HCC patients with paired
abuse and aflatoxin B (AFB ) exposure. [6,7] Most tumor and non-tumor tissues and 302 HCC patients with
1
1
previous studies examining miRNA profiles in HCC tumor tissues alone were analyzed in the current study.
tumor tissue or blood focused on investigation of
the main effects of aberrant miRNAs associated with Demographic, etiologic and clinical data include co-
cancer status without consideration of the potential variates of age, gender, race/ethnicity, height (m) and
influence of etiologic risk factors on miRNA levels weight (kg) at cancer diagnosis, body mass index (BMI,
2
that may bias the miRNA patterns observed in HCC kg/m ), HCC risk factors (alcohol consumption, HBV,
tumors with heterogeneous etiologies. That may HCV, NAFLD, mixed and none), tumor status (free vs.
be one reason for the discrepant results of previous not free), family history of cancer (no vs. yes), alpha
miRNA marker studies of HCC. Although some studies fetoprotein (AFP, ng/mL), histologic tumor grade
do examine miRNA profiles in HCC patients carrying (G1-G2 vs. G3-G4), the American Joint Committee
[11]
specific etiologies, [8-10] it is still unclear whether the on Cancer (AJCC) tumor-node-metastasis (TNM)
identified miRNAs are etiology-specific due to lack of (T0-T2 vs. T3-Tx), lymph node involvement (N0-N1
transverse comparisons with HCC patients carrying vs. Nx), pathological stage (stage I-II vs. stage III-IV),
other etiologic factors. Another challenge is the lack metastasis status (M0-M1 vs. Mx), vital status (alive
of a comparison of miRNA panels between HCC and vs. dead), survival days (either days to last follow-up
other solid tumor types, and no evidence to indicate or days to death). Other clinical variables (Child-Pugh
HCC tumor type specific miRNA alterations that may classification, vascular tumor invasion, adjuvant
limit future clinical application. In the current study, we treatment, surgical types and new tumor event after
integrate HCC etiologies and miRNA sequencing data initial treatment) were not analyzed in the current
from HCC and 8 other types of solid tumors in The study due to either a large amount of missing data or
Cancer Genome Atlas (TCGA) resource, and investigate small sample sizes in subgroups.
whether miRNA panels identified in HCC tumor are
organ specific and affected by important etiologic The level 3 (archive type) miRNA expression data were
factors. These results can be used for more precise generated from the Illumina HiSeq 2000 platform
clinical early diagnosis of HCC subtypes and screening (Illumina Inc., San Diego, CA) and annotated to
[12]
of high risk populations with specific HCC etiologies. reference miRBase v16 of UCSC hg19 alignments. A
total of 1,046 unique mature miRNAs were obtained.
METHODS The sequencing data are presented as raw read counts
and reads per million (RPM) mapped miRNAs reads.
Demographic, etiologies, clinical and miRNA data in The RPM indicates the expression level of miRNA
HCC patients from TCGA dataset and is calculated according to the formula: RPM =
TCGA is a comprehensive and coordinated project (N /N ) × 10 , N : number of reads mapped to
6
all
miR
miR
supported by the National Cancer Institute (NCI) the specific miRNA reference; N : total number of reads
all
and the National Human Genome Research Institute mapped in the sample. Because all demographic, clinical
152 Hepatoma Research | Volume 2 | June 1, 2016