The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis

Abstract

Recent studies have detailed the genomic landscape of primary endometrial cancers, but their evolution into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors, and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care

“…Intratumoral heterogeneity in EC has been described [113, 114], and might be predicted to weaken the utility of ProMisE. However, in the cases examined, although single nucleotide variations and copy number analysis revealed some diversity between anatomic sites within an individual (at time of diagnosis) the ProMisE molecular subgroup categorization was concordant across all tumor sites (6–14 anatomic sites examined per individual) [114].…”

The evolution of tumour phylogenetics: principles and practice

“…The mismatch between model and data can lead to discrepancies between evolutionary distance measures. For example, a 3 billion bp change induced by a whole-genome duplication will yield the same estimated evolutionary distance as 300,000 independent 10 kb changes, even though genome duplications are common events 21,22,147,160 and far more likely to occur than 300,000 independent 10 kb changes. That discrepancy will lead to large-scale changes being misinterpreted as being older than they actually are relative to localized changes, which could radically skew our trees.…”

“…Hypermutability phenotypes include chromosome instability (CIN) phenotypes that are characteristic of p53 dysfunction 16 , microsatellite instability (MIN) 17 , and elevated point mutation phenotypes, such as those arising from dysregulation of the APOBEC family of deaminase proteins 17,18 . Some variant types, such as copy number variants (CNVs), may be induced by multiple mechanisms — including breakage–fusion–bridge (BFB) cycles, missegregation of chromosomes, and genome doubling — each producing distinct scales and locations of aberrations 19–22 . Other tumour-specific mutational mechanisms include the following: kataegis 23 , in which single nucleotide variants (SNVs) occur at a high rate in a small chromosomal region; chromothripsis 24 , in which a single chromosome shatters and reassembles in a seemingly random manner; and chromoplexy 25 , a complex structural variation characterized by chains of BFB-induced chromosome rearrangements occurring in successive mitoses.…”

Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times

“…11 ARID1A inactivating mutations are associated with loss of the corresponding protein. 12 Genomic deletions in CDKN2A can be assayed using dual-color FISH. 13 An analysis of the sequenced metastatic PanNETs revealed loss of H3K36me3 and ARID1A by immunohistochemistry and deletions for CDKN2A by dual-color FISH had a 100% concordance with alterations in their respective genes (Supplementary Figure 2).…”