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Study Uncovers Curable Molecular Subtype of Colorectal Cancers Metastasized to Liver

NEW YORK (GenomeWeb) – A University of Chicago-led team has identified a form of colorectal cancer (CRC) forming a localized metastatic tumor in the liver that is highly treatable.

Using a combination of RNA sequencing, targeted panel sequencing, microRNA analyses, and/or microsatellite instability assays, the researchers profiled samples from as many as 121 individuals with liver metastases stemming from primary CRC. The findings, published online today in Nature Communications, highlighted low-risk "oligometastatic" CRC liver tumors marked by low clinical risk scores and either low- or intermediate-risk molecular subtypes.

"Our findings indicate a molecular basis for oligometastasis that is predictive of clinical outcome and complementary to established clinical risk factors associated with long-term survival following hepatic resection," senior author Ralph Weichselbaum, a radiation and cellular oncology researcher at the University of Chicago, and his colleagues wrote. The authors noted that such results "may have important clinical implications in the selection of local therapy for those patients with potentially curable oligometastatic disease from those whose few metastases are part of a large cascade of widespread disease."

For their analyses, the researchers started with a set of 134 cases involving liver metastases from primary CRC, ultimately profiling molecular patterns in 121 of the metastatic tumor samples. Along with Affymetrix array-based miRNA profiling on 116 samples, for example, they used Illumina HiSeq instruments to do transcriptome sequencing on 95 metastatic tumors.

To that, the team added OncoPlus panel sequencing on matched tumor and normal samples from 59 of the cases, and used Promega MSI 1.2 clinical assays to assess microsatellite instability patterns in 89 of the metastatic tumor samples. The subset tumor classification strategy was informed by available CRC genomic data generated for efforts such as the Cancer Genome Atlas.

From these data, the researchers identified three molecular subtypes for the CRC metastases in the liver, including a form of oligometastatic disease that coincided with better overall survival times. A subset of more favorable CRC liver metastasis cases showed "microsatellite instability-independent" activation of interferon and other immune signaling pathways, paired with mutations in genes such as NRAS, CDK12, and EBF1, the researchers reported, while an intermediate tumor subtype had VEGFA amplifications in combination with NOTCH1 mutations, PIK3C2B mutations, and E2F/MYC pathway activation — a molecular profile dubbed "canonical." Riskier, "stromal" CRC liver metastatic tumors contained VEGFA amplifications coupled with stromal, mesenchymal, and angiogenic molecular signatures.

The team noted that individuals with favorable or intermediate tumor types and low clinical risk scores appeared to have 10-year average survival rates of 94 percent. In contrast, 45 percent of individuals survived for 10 years when their metastases fell in the intermediate canonical subtype and had high clinical risk scores or belonged to the unfavorable stromal tumor subtypes with low clinical risk.

The 10-year survival rates were even more dire — just 19 percent — for cases with stromal CRC liver metastases paired with high clinical risk scores, the researchers found, demonstrating the complementary nature of the molecular subtype and clinical risk score data. 

More broadly, the authors noted that the current findings "provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer," and "may be applicable to many patients with metastatic cancer."

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