Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sci Adv. 2022 Jun 24;8(25):eabn9699. doi: 10.1126/sciadv.abn9699. Epub 2022 Jun 22.
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.
Hurthle 细胞癌 (HCCs) 表现出两种特殊的基因型：线粒体 DNA (mtDNA) 的近同质突变和全基因组杂合性丢失 (gLOH)。为了了解这些遗传改变的表型后果，我们分析了 HCC 和其他甲状腺癌的基因组、代谢组和免疫表型数据。mtDNA 突变和柠檬酸池的深度耗竭在 HCC 和其他甲状腺恶性肿瘤中都很常见，这表明甲状腺癌广泛具备了在三羧酸循环受损时存活的能力，而 NADH 依赖性赖氨酸降解途径还原形式的代谢物仅在 HCC 中升高。gLOH 的存在与代谢表型无关，但与免疫浸润减少有关，这表明 gLOH 通过部分免疫抑制获得选择性优势。无监督多模态聚类揭示了具有不同临床、代谢组学和微环境表型但重叠基因型的 HCC 四个聚类。这些发现描绘了 HCC 的代谢和微环境景观，并揭示了基因型、代谢和癌症微环境之间的相互作用。
