NEW YORK (GenomeWeb) – A new genomic and transcriptomic analysis has found that subtypes of combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) have distinct molecular features.
Whether cHCC-ICC is its own type of rare liver cancer or is a form of either hepatocellular carcinoma or intrahepatic cholangiocarcinoma has been unclear. Researchers led by Peking University's Ning Zhang sequenced the genomes and transcriptomes of 133 cHCC-ICC cases, including ones belonging to the separate, combined, and mixed cHCC-ICC subtypes. As they reported in Cancer Cell today, they found that the combined and mixed cHCC-ICCs have different mutational landscapes. Still, the researchers found that the expression of the protein nestin might serve as a biomarker for all cHCC-ICCs.
"This finding may direct future therapeutic choices for cHCC-ICC patients," Zhang and colleague wrote in their paper.
In their pan-Asia, multi-center study they analyzed 133 cHCC-ICC samples using a combination of whole-exome, whole-genome, RNA, and single-nucleus sequencing. Based on established criteria, they were able to categorize 121 of these cHCC-ICC cases as separate, combined, or mixed cHCC-ICC subtypes.
Among all these samples, the most significantly mutated genes were TP53, AXIN1, and RB1, while signaling pathways involved in histone modification and DNA methylation were commonly altered in cHCC-ICC. In addition, the researchers noted noncoding and structural variation, including variations affecting the TERT promoter and fusion genes as well as focally amplified and deleted regions.
But these mutational signatures varied by cHCC-ICC subtype, the researchers noted. Using the computational tool SigProfiler, they uncovered three mutational signatures within their sample set that largely correlated with the COSMIC signatures 5, 22, and 24.
They also compared the mutational landscape of these cHCC-ICC samples with those found in HCC and ICC, finding that TP53 was mutated in nearly half of cHCC-ICC cases, much higher than in either HCC or ICC tumors, while cHCC-ICC cases had lower rates of CTNNB1 mutations than HCCs and lower rates of KRAS mutations than ICC.
Likewise, at the transcriptional level, the researchers noted that their samples and ICC and HCC samples clustered into four groups. Cluster 1, for instance, included ICC cases, but also combined cHCC-ICC cases. It was also enriched for KRAS mutations, but depleted of TERT promoter mutations. Cluster 2, meanwhile, was enriched for Hoshida-S2 HCC cases as well as mixed cHCC-ICC cases, and was marked by increased TP53 mutations.
This, the researchers noted, indicates that mixed and combined cHCC-ICC are distinct subtypes with different molecular features and that patients with these subtypes could benefit from different therapeutic strategies.
They further suggested that the previous controversy over whether or not cHCC-ICC is a distinct type of liver cancer could be due to previous work only sampling one of these cHCC-ICC subtypes that resembled ICC or HCC to a certain extent.
Still, both mixed and combined cHCC-ICCs are associated with a stem-like feature and exhibit poor prognosis, the researchers noted. Both types have high expression of nestin, a marker for the bipotent progenitor oval cell, which may give cancer cells high cellular plasticity. When they compared Nestin levels in the various cHCC-ICC subtypes to HCC and ICC, they found that more than 80 percent of the cHCC-ICC samples had higher nestin levels than the HCC or ICC samples.
This, they said, suggests nestin might be a biomarker for diagnosing cHCC-ICC.