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Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities.

ABSTRACT: Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: β-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions.

SUBMITTER: Kalasekar SM

PROVIDER: S-EPMC8582820 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Endometrial cancer (EC) is the most common female genital malignancy and the fourth most common cancer in women in the developing world1. EC has been traditionally classified into two main groups with different clinical, pathological and molecular features2,3. Type I or endometrioid endometrial carcinomas (EECs) account for about 75% of the cases and are typically estrogen-related and low-grade tumors with good prognosis that coexist or are preceded by endometrial hyperplasia, mainly diagnosed in perimenopausal women. In contrast, type II or non-endometrioid endometrial carcinomas (NEECs) are high-grade aggressive tumors associated with endometrial atrophy and poor prognosis, unrelated to estrogen and diagnosed in older women. These comprise several histological subtypes, being the most common the serous carcinomas (SEC)4. In recent years numerous large-scale studies of primary endometrioid and serous tumors have been performed5, revealing new mutated genes and establishing a new molecular subclassification based on the results obtained by The Cancer Genome Atlas (TCGA) consortium6, which implies different clinical outcomes. More recently, the genomic evolution of EC has been analyzed through a comparative study of samples from endometrial atypical hyperplasia, primary tumors and paired metastases7, revealing the presence of intratumor heterogeneity as previously described in primary EC and other tumor types8,9. However an in-depth study considering multiple regions from primary tumor and paired metastases has not been performed up to now to our knowledge. Here we analyze by whole-exome sequencing (WES), massive parallel targeted sequencing and array comparative genomic hybridization (aCGH) the clonal evolution and intratumor heterogeneity of 7 endometrioid and 3 serous metastatic endometrial carcinomas. Different locations from the primary tumor as well as from their paired metastases were included in the study, allowing the reconstruction of the spatial and temporal phylogenetic evolution of the tumor. Different phylogenetic evolution patterns were identified, independently of the classical histological or molecular classification of the tumor, although similar patterns were found in ovarian metastasis and recurrent disease.

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Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities.

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