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Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer

Abstract

Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.

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Figure 1: Comparison of the genomic landscape of plasmacytoid variant bladder cancers to that of urothelial carcinoma, NOS, cancers.
Figure 2: Clinical and biological effects of CDH1 loss.

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References

  1. Siegel, R.L., Miller, K.D. & Jemal, A. CA Cancer J. Clin. 65, 5–29 (2015).

    Article  Google Scholar 

  2. Amin, M.B. Mod. Pathol. 22 (suppl. 2), S96–S118 (2009).

    Article  Google Scholar 

  3. Chalasani, V., Chin, J.L. & Izawa, J.I. Can. Urol. Assoc. J. 3 (suppl. 4), S193–S198 (2009).

    PubMed  PubMed Central  Google Scholar 

  4. Dayyani, F. et al. J. Urol. 189, 1656–1661 (2013).

    Article  Google Scholar 

  5. Kaimakliotis, H.Z. et al. Urology 83, 1112–1116 (2014).

    Article  Google Scholar 

  6. Keck, B. et al. BMC Cancer 13, 71 (2013).

    Article  CAS  Google Scholar 

  7. Nigwekar, P. et al. Am. J. Surg. Pathol. 33, 417–424 (2009).

    Article  Google Scholar 

  8. Cancer Genome Atlas Network. Nature 490, 61–70 (2012).

    Article  Google Scholar 

  9. Cancer Genome Atlas Research Network. Nature 513, 202–209 (2014).

  10. Graff, J.R. et al. Cancer Res. 55, 5195–5199 (1995).

    CAS  PubMed  Google Scholar 

  11. Grady, W.M. et al. Nat. Genet. 26, 16–17 (2000).

    Article  CAS  Google Scholar 

  12. Corso, G. et al. J. Clin. Oncol. 31, 868–875 (2013).

    Article  CAS  Google Scholar 

  13. Johnson, B.E. et al. Science 343, 189–193 (2014).

    Article  CAS  Google Scholar 

  14. Li, H. & Durbin, R. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  Google Scholar 

  15. McKenna, A. et al. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  Google Scholar 

  16. DePristo, M.A. et al. Nat. Genet. 43, 491–498 (2011).

    Article  CAS  Google Scholar 

  17. Cibulskis, K. et al. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  Google Scholar 

  18. Ye, K., Schulz, M.H., Long, Q., Apweiler, R. & Ning, Z. Bioinformatics 25, 2865–2871 (2009).

    Article  CAS  Google Scholar 

  19. Won, H.H., Scott, S.N., Brannon, A.R., Shah, R.H. & Berger, M.F. J. Vis. Exp. 80, e50710 (2013).

    Google Scholar 

  20. Cheng, D.T. et al. J. Mol. Diagn. 17, 251–264 (2015).

    Article  CAS  Google Scholar 

  21. Cerami, E. et al. Cancer Discov. 2, 401–404 (2013).

    Article  Google Scholar 

  22. Rohde, C., Zhang, Y., Reinhardt, R. & Jeltsch, A. BMC Bioinformatics 11, 230 (2010).

    Article  Google Scholar 

  23. Sanjana, N.E., Shalem, O. & Zhang, F. Nat. Methods 11, 783–784 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Translational and Integrative Medicine Research Fund award (H.A.A.), Cycle for Survival (H.A.A. and B.S.T.), the Josie Robertson Foundation (B.S.T.) and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. This study was also funded in part by the Sloan Kettering Institute for Cancer Research Cancer Center Support Grant (P30CA008748).

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Authors and Affiliations

Authors

Contributions

S.N.S., R.R., M.F.B., A.V., M.E.A. and B.S.T. performed sequencing and analyzed the data. A.B., E.C.Z. and I.O. acquired clinical data and performed statistical analyses. B.H.L., E.J.J. and S.P.G. performed the in vitro experiments. H.A.A., R.M., A. Gopalan, Y.-B.C., S.W.F., S.K.T., A. Gandhi, J.H. and V.E.R. reviewed the pathology and identified tumor specimens for analysis. G.I., E.K.C., N.B.D. and A. Gandhi performed specimen collection and DNA extraction. H.A.A., G.I., B.H.L., G.D., J.E.R., B.H.B., D.F.B., M.F.B., V.E.R., B.S.T. and D.B.S. were involved with the conception and design of the study. All authors assisted with drafting and critically revising the manuscript.

Corresponding author

Correspondence to David B Solit.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 CDH1 truncating alterations were detected in all six plasmacytoid-variant bladder tumors analyzed by whole-exome sequencing.

Whole-exome sequencing of six plasmacytoid-variant bladder tumors (left) with copy number analysis of the CDH1 locus for two representative cases (right). All six tumors analyzed harbored truncating loss-of-function mutations in CDH1. Evidence for copy-neutral loss of the wild-type allele and loss of heterozygosity was observed in the two samples shown (asterisks above heat map).

Supplementary Figure 2 Pattern of CDH1 alterations and select co-alterations in plasmacytoid-variant bladder cancers, lobular breast carcinomas and diffuse gastric carcinomas.

With the exception of CDH1 alterations, the pattern of genetic co-alterations in lobular breast and diffuse gastric carcinomas was distinct from that of plasmacytoid-variant bladder cancer. Somatic mutation data for the lobular breast carcinoma and diffuse gastric carcinomas was derived from The Cancer Genome Atlas.

Supplementary Figure 3 Phylogenetic tree depicting the divergent evolution of plasmacytoid-variant carcinoma and urothelial carcinoma, NOS, histologies within a tumor with distinct histologic regions.

Exon capture and deep sequencing of two adjacent portions of a bladder tumor harboring distinct regions of plasmacytoid-variant and urothelial carcinoma, NOS, histologies. CDKN2A and PIK3C2G alterations were shared by plasmacytoid-variant histology and urothelial carcinoma, NOS, areas within the same tumor, suggesting that these are truncal alterations occurring within a common precursor cell. However, a CDH1 frameshift mutation was unique to plasmacytoid-variant histology, and the remaining genetic alteration profiles of the two histologic components were distinct. Magenta and green lines in the phylogenetic tree indicate plasmacytoid-variant and urothelial carcinoma, NOS, histologies, respectively.

Supplementary Figure 4 CDH1 promoter hypermethylation is a mechanism for loss of expression of E-cadherin in plasmacytoid-variant bladder cancer.

Bisulfite sequencing of the CDH1 promoter CpG island showed hypermethylation in four of five CDH1–wild type plasmacytoid-variant bladder tumors. Representative urothelial carcinoma, NOS, specimens (U1, U2) that were subjected to bisulfite sequencing are shown to lack CDH1 promoter hypermethylation. A schematic of the CpG island is depicted with red circles representing methylated CpG sites.

Supplementary Figure 5 E-cadherin expression is absent in the invasive component of plasmacytoid-variant tumors.

Low magnification H&E showing the in situ and invasive regions of plasmacytoid-variant tumors is displayed on the left. High-magnification views with E-cadherin IHC of each of these regions are shown on the right. E-cadherin expression is retained within the in situ component and is absent from the invasive regions of this tumor.

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Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1 and 2. (PDF 824 kb)

Supplementary Data set

Western blots used in Figure 2c. (PDF 359 kb)

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Al-Ahmadie, H., Iyer, G., Lee, B. et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genet 48, 356–358 (2016). https://doi.org/10.1038/ng.3503

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