SCNC patterns of gene expression, methylation, and mutations are convergent.

  • Major Finding: SCNC patterns of gene expression, methylation, and mutations are convergent.

  • Concept: SCNCs’ and hematopoietic cancers’ drug susceptibilities and functional dependencies overlap.

  • Impact: Patients with SCNCs may respond to drugs effective in hematopoietic malignancies.

Small-cell neuroendocrine cancers (SCNC) are aggressive, with five-year survival rates of less than 20% for SCN lung and prostate cancers. Adenocarcinomas can transdifferentiate into SCNCs, which may represent a mechanism of escape from targeted therapies. Balanis, Sheu, and colleagues characterized the molecular signatures of several SCNCs and identified their susceptibilities to an extensive list of drugs. Unsupervised principal-component analysis of RNA-sequencing data from lung adenocarcinomas, castration-resistant prostate adenocarcinomas, small-cell lung cancers, and castration-resistant neuroendocrine prostate cancer tumor biopsies revealed differences and similarities in these cancers’ gene expression profiles, with similarities increasing substantially as adenocarcinomas progressed toward SCN states. These results provide a molecular signature underscoring what is seen in pathology examination of SCNC tumors across tissue types. Gene sets related to neuron development and function, splicing, and the cell cycle were enriched in SCNCs, whereas gene sets related to cell adhesion and immune response were de-enriched. The DNA methylation signatures of progression to SCN status in lung and bladder cancers were similar to one another and characterized by enrichment of neuronal development gene sets. Further, patterns of copy-number alterations were consistent across lung and prostate SCN tumor types. Indicating the broader relevance of this work, SCNC-like tumors (based on gene expression patterns) were identified in a group of purportedly non-SCN tumors representing 21 epithelial tumor types; most were high-grade tumors and associated with a reduction in patient survival. Among non-SCN tumors, metastatic tumors were more likely to exhibit the SCN gene-expression signature. Mutations associated with SCN status were also identified: In addition to known SCNC-associated genes such as TP53 and RB1, there were associations between SCNC and mutations in FOXA1 and NRAS (neuroblastoma-RAS), whereas mutations in KRAS were associated with non-SCNC status. Unexpectedly, there were substantial similarities between SCNCs and hematopoietic cancers compared to non-blood epithelial cancers; for example, SCNCs and hematopoietic cancers shared projection-based protein-expression profiles and drug sensitivities. This work suggests avenues for research on drugs that may be effective in treating SCNCs.

Balanis NG, Sheu KM, Esedebe FN, Patel SJ, Smith BA, Park JW, et al. Pan-cancer convergence to a small-cell neuroendocrine phenotype that shares susceptibilities with hematological malignancies. Cancer Cell 2019;36:17–34.

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