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

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Abstract

Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers 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 The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both 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 in endometrial cancers and relative homogeneity across metastatic sites.

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Figure 1: Samples assessed.
Figure 2: Somatic genetic alterations in CAHs and primary and metastatic endometrial carcinomas.
Figure 3: Heterogeneity among somatic mutations.
Figure 4: Phylogenetic trees for tumors with more than one metastasis.

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Acknowledgements

We dedicate this manuscript to Helga Birgitte Salvesen, who unexpectedly passed away before its publication. She was a tremendously generous and insightful colleague and a dear friend. We will all miss her dearly.

We thank E. Valen, B. Edvardsen, K. Madissoo, R. Kopperud and B. Nordanger for excellent technical assistance. This study was supported by the Research Council of Norway, the Norwegian Cancer Society, Helse Vest, the University of Bergen, the Bergen Research Foundation, the National Institutes of Health (award numbers T32GM007753, 5R01CA188228 and 1F30CA192725) and the Novartis Institutes for Biomedical Research.

Author information

E.A.H. and H.B.S. initiated the study, and W.J.G., E.A.H., S.L.C., R.B. and H.B.S. designed the study. E.A.H., M.K.H., A.B., H.M.J.W., I.M.S., K.K.M., J.T., K.W., L.B. and H.B.S. performed sample collection, annotation and curation. W.J.G., E.A.H., A.T.-W., A.D.C., F.H., T.I.Z., K.M.S., K.K., J.A.W., M.S.L., S.L.C., R.B. and H.B.S. performed the data analyses. E.A.H., K.M.S. and C.K. performed validation and microsatellite instability and immunohistochemistry experiments. W.J.G., E.A.H., M.R., A.C., K.K.M., J.T., C.K., M.G., E.H., O.K.V., M.S.L., G.G., S.L.C., R.B. and H.B.S. contributed reagents and algorithms. All authors critically revised the manuscript.

Correspondence to Erling A Hoivik or Scott L Carter or Rameen Beroukhim.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16. (PDF 47493 kb)

Supplementary Table 1

Clinical background data on patient cases. (XLSX 32 kb)

Supplementary Table 2

Validation of sequencing results. (XLSX 36 kb)

Supplementary Table 3

Significantly mutated genes. (XLSX 2234 kb)

Supplementary Table 4

Kaplan–Meier survival analysis. (XLSX 11 kb)

Supplementary Table 5

Gene mutation correlations. (XLSX 114 kb)

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Gibson, W., Hoivik, E., Halle, M. et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet 48, 848–855 (2016) doi:10.1038/ng.3602

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