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Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hurthle cell carcinoma.

ABSTRACT: Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). To understand the phenotypic consequences of these genetic alterations, we analyzed genomic, metabolomic, and immunophenotypic data of HCC and other thyroid cancers. Both mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment, whereas metabolites in the reduced form of NADH-dependent lysine degradation pathway were elevated exclusively in HCC. The presence of gLOH was not associated with metabolic phenotypes but rather with reduced immune infiltration, indicating that gLOH confers a selective advantage partially through immunosuppression. Unsupervised multimodal clustering revealed four clusters of HCC with distinct clinical, metabolomic, and microenvironmental phenotypes but overlapping genotypes. These findings chart the metabolic and microenvironmental landscape of HCC and shed light on the interaction between genotype, metabolism, and the microenvironment in cancer.

SUBMITTER: Ganly I

PROVIDER: S-EPMC9216518 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma.

Ganly Ian I Liu Eric Minwei EM Kuo Fengshen F Makarov Vladimir V Dong Yiyu Y Park Jinsung J Gong Yongxing Y Gorelick Alexander N AN Knauf Jeffrey A JA Benedetti Elisa E Tait-Mulder Jacqueline J Morris Luc G T LGT Fagin James A JA Intlekofer Andrew M AM Krumsiek Jan J Gammage Payam A PA Ghossein Ronald R Xu Bin B Chan Timothy A TA Reznik Ed E

Science advances 20220622 25

Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). To understand the phenotypic consequences of these genetic alterations, we analyzed genomic, metabolomic, and immunophenotypic data of HCC and other thyroid cancers. Both mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to ...[more]

PMID: 35731870

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Project description:Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.SignificanceThe immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome.

Project description:BackgroundIncreasing evidence supports that immune cell infiltration (ICI) patterns play a key role in the tumor progression of lung squamous cell carcinoma (LUSC). However, to date, the immune infiltration picture of LUSC has not been elucidated.MethodTCGA was used to download multiomics data from LUSC samples. At the same time, we included two datasets on lung squamous cell carcinoma, GSE17710 and GSE157010. To reveal the landscape of tumor immune microenvironment (TIME), the ESTIMATE algorithm, ssGSEA approach, and CIBERSORT analysis are used. To quantify the ICI pattern in a single tumor, consistent clustering is used to determine the LUSC subtype based on the ICI pattern, and principal component analysis (PCA) is used to obtain the ICI score. The prognostic value of the Kaplan-Meier curves is confirmed. GSEA (Gene Set Enrichment Analysis) was used to perform functional annotation. To investigate the immunotherapeutic effects of the ICI score, the immunophenotyping score (IPS) is used. Finally, analyze the mutation data with the "maftools" R package.ResultsWe identified four different immune infiltration patterns with different prognosis and biological characteristics in 792 LUSC samples. The identification of ICI patterns in individual tumors developed under ICI-related characteristic genes based on the ICI score helps to analyze the biological process, clinical results, immune cell infiltration, immunotherapy effects, and genetic variation. Immune failure is indicated by a high ICI score subtype marked by immunosuppression. Patients with low ICI scores have an abundance of efficient immune cells, which corresponds to the immunological activation phenotype and may have therapeutic benefits. The immunophenotypic score was used as a surrogate indicator of immunotherapy results, and samples with low ICI scores obtained significantly higher immunophenotypic scores. Finally, the relationship between the ICI score and tumor mutation burden (TMB) was proven.ConclusionThis study fully clarified the indispensable role of the ICI model in the complexity and diversity of TIME. The quantitative identification of ICI patterns in a single tumor will help draw the picture of TIME and further optimize precision immunotherapy.

Project description:Background: Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) are rare and aggressive thyroid cancers with limited published data comparing their outcomes or regarding their subtypes. The aim of this study was to describe clinicopathological features and compare clinical outcomes of patients with FTC and HCC based on the 2017 World Health Organization definition and extent of vascular invasion (VI). Methods: We retrospectively studied 190 patients with HCC and FTC primarily treated with surgery at Memorial Sloan Kettering Cancer Center between 1986 and 2015. Patients were classified as minimally invasive (MI), encapsulated angioinvasive with focal VI (EA-FVI), encapsulated angioinvasive with extensive VI (EA-EVI), and as widely invasive (WI). To compare clinical outcomes, patients were grouped as follows: group 1 = FTC-MI and FTC EA-FVI, group 2 = FTC EA-EVI and FTC-WI, group 3 = HCC-MI and HCC EA-FVI, group 4 = HCC EA-EVI and HCC-WI. Outcomes of interest were overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and distant recurrence-free survival (DRFS). Outcomes were determined using the Kaplan-Meier method and compared with log-rank test. Results: Patients with HCC (n = 111) were more likely to be older than 55 years old (59% vs. 27%, p < 0.001) with a tendency to present with more extensive VI (33% vs. 19%, p = 0.07) compared with FTC (n = 79). Comparing groups 1, 2, 3, and 4, group 4 patients were more likely to recur (DFS 98%, 93%, 98% vs. 73%, respectively, p = 0.0069). There was no statistically significant difference in OS, DSS LRRFS, or DRFS. Stratified by extent of VI (no, focal, and extensive VI), patients with extensive VI were more likely to recur (RFS 100%, 95%, 77%, p = 0.0025) and had poorer distant control (DRFS: 100%, 95%, 80%, p = 0.022), compared with patients absent or focal VI. Conclusions: Accurate assessment of the extent of VI and tumor phenotype (follicular vs. Hurthle) are essential in identifying patients at higher risk of recurrence.

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Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hurthle cell carcinoma.

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Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma.

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