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.

Genomic Landscapes and Tumor Evolution in Metastatic Gynecological Cancers

“…The high proportion of monophyletic evolution in endometrial cancer has recently been confirmed though whole exome sequencing analysis of metastases with corresponding primary tumor in a similar cohort consisting of nine endometrial cancer patients, where the majority of cases fitted into to the evolutionary model of monophyly (46). These studies found no evidence of reseeding (29,46). Interestingly, a study on metastatic prostate cancer, with survival probabilities resembling endometrial cancer, was also determined to be mainly monophyletic, while that of the more aggressive pancreatic cancer was polyphyletic.…”

“…However, in the seventh case, one of the metastases was more closely related to the primary tumor than to the other metastases, a case of polyphyly, because of the presence of multiple origins (Figure 3B). The high proportion of monophyletic evolution in endometrial cancer has recently been confirmed though whole exome sequencing analysis of metastases with corresponding primary tumor in a similar cohort consisting of nine endometrial cancer patients, where the majority of cases fitted into to the evolutionary model of monophyly (46). These studies found no evidence of reseeding (29,46).…”

“…Multiple studies have addressed the relationship of synchronous cancers with endometrial and ovarian lesions through different sequencing approaches, including panel-sequencing and whole exome sequencing approaches (29,(51)(52)(53)(54)(55). It is noted that some cases diagnosed with synchronous cancers do not have shared genomic alterations, suggesting either a true (29,46). Tumor evolutionary phylogenetic trees constructed from somatic mutations are displayed to the left, with accompanying models to the right.…”

“…B, Alternatively, multiple clones seed the different metastases in the polyphyly model. Current data has demonstrated that the monophyletic model is the dominating and most likely route of metastatic spread(29,46). Tumor evolutionary phylogenetic trees constructed from somatic mutations are displayed to the left, with accompanying models to the right.…”

Pattern A endocervical adenocarcinomas with ovarian metastasis are indolent and molecularly distinct from destructively invasive adenocarcinomas

“…[18][19][20] To explain this phenomenon, it has been hypothesised that in in those patients with indolent tumour behaviour the ovarian metastases occur through fallopian tube migration at early stages of endometrial cancer progression. 21 We postulate that the model of ovarian involvement by endometrial endometrioid carcinomas portending a good prognosis can also be applied to pattern A HPVA with ovarian metastasis. To this end, we document the clinical, pathological and molecular characteristics of an institutional cohort of patients with pattern A HPVA and ovarian spread, comparing them to a group of metastatic patterns B and C HPVAs, focusing upon genomic alterations of both primary cervical tumours and their matched metastasis, as well as patient outcome.…”