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Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression.

ABSTRACT: Analyzing different tumor regions by next generation sequencing allows the assessment of intratumor genetic heterogeneity (ITGH), a phenomenon that has been studied widely in some tumor types but has been less well explored in endometrial carcinoma (EC). In this study, we sought to characterize the spatial and temporal heterogeneity of 9 different ECs using whole-exome sequencing, and by performing targeted sequencing validation of the 42 primary tumor regions and 30 metastatic samples analyzed. In addition, copy number alterations of serous carcinomas were assessed by comparative genomic hybridization arrays. From the somatic mutations, identified by whole-exome sequencing, 532 were validated by targeted sequencing. Based on these data, the phylogenetic tree reconstructed for each case allowed us to establish the tumors' evolution and correlate this to tumor progression, prognosis, and the presence of recurrent disease. Moreover, we studied the genetic landscape of an ambiguous EC and the molecular profile obtained was used to guide the selection of a potential personalized therapy for this patient, which was subsequently validated by preclinical testing in patient-derived xenograft models. Overall, our study reveals the impact of analyzing different tumor regions to decipher the ITGH in ECs, which could help make the best treatment decision.

SUBMITTER: Mota A

PROVIDER: S-EPMC8956509 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression.

Mota Alba A Oltra Sara S SS Selenica Pier P Moiola Cristian P CP Casas-Arozamena Carlos C López-Gil Carlos C Diaz Eva E Gatius Sonia S Ruiz-Miro María M Calvo Ana A Rojo-Sebastián Alejandro A Hurtado Pablo P Piñeiro Roberto R Colas Eva E Gil-Moreno Antonio A Reis-Filho Jorge S JS Muinelo-Romay Laura L Abal Miguel M Matias-Guiu Xavier X Weigelt Britta B Moreno-Bueno Gema G

Oncogene 20220210 13

Analyzing different tumor regions by next generation sequencing allows the assessment of intratumor genetic heterogeneity (ITGH), a phenomenon that has been studied widely in some tumor types but has been less well explored in endometrial carcinoma (EC). In this study, we sought to characterize the spatial and temporal heterogeneity of 9 different ECs using whole-exome sequencing, and by performing targeted sequencing validation of the 42 primary tumor regions and 30 metastatic samples analyzed. ...[more]

PMID: 35145232

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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.

Project description:BackgroundIntratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.MethodsTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.ResultsPhylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.ConclusionsIntratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

Project description:Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, while the other half was used for DNA and RNA purification. For two patients, lymph node metastases were analyzed. Somatic mutations were called from whole exome sequencing data. Each tumor contained mutations shared across all biopsies and spheroids, including major CRC drivers such as APC, KRAS, and TP53. At the same time, all tumors exhibited ITH on both mutation and copy number level. The concordance between biopsies and spheroids ranged between 40 and 70% for coding mutations. For three patients, the biopsy and spheroid from matching areas clustered together, meaning that the spheroid resembled the area of origin more than the other areas. However, all biopsies and spheroids contained private mutations. Therefore, multiple cultures from spatially distinct sites of the tumor increase the insight into the genetic profile of the entire tumor. Molecular subtypes were called from RNA sequencing data. When based on transcripts from both cancer and noncancerous cells, the subtypes were largely independent of sampling site. In contrast, subtyping based on cancer cell transcripts alone was dependent on sample site and genetic ITH. In conclusion, all examined CRC tumors showed genetic ITH. Spheroid cultures partly reflected this ITH, and having multiple cultures from distinct tumor sites improved the representation of the genetic tumor subclones. This should be taken into account when establishing patient-derived models for drug screening.

Dataset Information

Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression.

Publications

Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression.

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