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Mol Cancer Res. 2019 Jan 4. pii: molcanres.1178.2018. doi: 10.1158/1541-7786.MCR-18-1178. [Epub ahead of print]

Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma.

Author information

1
Department of Pathology, University of Michigan-Ann Arbor.
2
Bioinformatics, University of Michigan-Ann Arbor.
3
Michigan Center for Translational Pathology, University of Michigan-Ann Arbor.
4
Computational Medicine and Bioinformatics, University of Michigan Medical School.
5
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School.
6
Pathology, University of Michigan-Ann Arbor.
7
Department of Anatomic Pathology, Mayo Clinic.
8
Department of Pathology, Department of Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan-Ann Arbor tomlinss@med.umich.edu.

Abstract

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development-like in many cancers-are incompletely understood. Hence, here we performed multi-region, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially-defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. While substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole transcriptome profiling of co-isolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1 mutant vs. wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens. Implications: Multi-region profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.

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