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Unique MicroRNA Expression Signature Predicts Survival, Metastases and Recurrence of HCC

ABSTRACT: In this study we investigated the miRNA expression profile of Hepatocellular carcinoma (HCC) specimens from radical resection. We developed a unique 20 miRNA signature that could significantly distinguish HCC venous metastasis from metastasis-free HCC. In contrast to HCC staging systems, this signature was capable of predicting survival and recurrence of HCC patients with multinodular or solitary tumors, including those with early-stage disease. Moreover, the signature was an independent and significant predictor of patient prognosis and relapse when compared to other available clinical parameters. Our study suggests that these 20 miRNAs can enable HCC prognosis and may have clinical utility for the advance identification of HCC patients with a propensity towards metastasis/recurrence. Keywords: disease state design

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE6857 | GEO | 2008/01/14

SECONDARY ACCESSION(S): PRJNA99101

REPOSITORIES: GEO

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Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.

Project description:BACKGROUND & AIMS: Despite the increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the balance of the tumor-associated myeloid response and its translational value. We aimed to construct a simple and reliable signature of local myeloid responses in hepatocellular carcinoma (HCC). METHODS: Using in situ immunohistochemistry (IHC), we assessed myeloid features that revealed the distribution of major myeloid subtypes in both the peri- and intratumoral regions of HCC. A signature was constructed using an L1-penalized Cox regression model based on the postsurgery recurrence data from a training subset (n = 244) that was validated in the testing subset (n = 244) and independent internal (n = 341) and external (n = 348) cohorts. Multiplexed immunofluorescence staining, flow cytometry and transcriptomic analyses were performed to examine the immunological deviations associated with the myeloid signature. Further, we built nomograms to provide a more robust and personalized prognosis for HCC patients. RESULTS: A 2-feature-based, myeloid-specific prognostic signature, namely the myeloid response score (MRS), was constructed. The increase in the MRS was associated with a change in the predominant myeloid populations from CD169+ macrophages (Mφs) in MRSlow HCCs to CD15+CD11b+ neutrophils and CD11b+CD169- Mφs in MRShigh tumors, suggesting a shift in the balance of the myeloid response from antitumor to protumor activities. This alteration was also accompanied by the enhancement of CD8+ T cell exhaustion patterns, including impaired cytotoxic potential and elevated programmed cell death protein 1 (PD-1) expression. The MRS and the MRS-based nomograms had higher accuracy for predicting recurrence and patient survival than the Barcelona Clinic Liver Cancer (BCLC) and tumor-node-metastasis (TNM) staging systems and were validated in a multicenter cohort of HCC patients. Moreover, in a separate cohort of 51 patients, we provided evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC. CONCLUSIONS: We identified and validated a descriptive and prognostic myeloid signature for HCC. HCC tissues with low, intermediate, and high MRS estimates represent tumors with immunocompetent, immunodeficient, and immunosuppressive subtypes, respectively. This technically simple and reliable myeloid signature shows remarkable prognostic potential for HCC after resection and could serve as the basis for the stratification of HCC immune subtypes to aid in a wide range of clinical decisions.

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Unique MicroRNA Expression Signature Predicts Survival, Metastases and Recurrence of HCC

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