RESUMO
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is first line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by immunohistochemistry and RNA-Seq, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacological ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5/52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacological ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Further, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.
Assuntos
Neoplasias Pulmonares , Neoplasias da Próstata , Masculino , Humanos , Quinase do Linfoma Anaplásico/genética , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/genética , Neoplasias da Próstata/tratamento farmacológicoRESUMO
BACKGROUND: Plasma-based cell-free DNA is an attractive biospecimen for assessing somatic mutations due to minimally-invasive real-time sampling. However, next generation sequencing (NGS) of cell-free DNA (cfDNA) may not be appropriate for all patients with advanced prostate cancer (PC). METHODS: Blood was obtained from advanced PC patients for plasma-based sequencing. UW-OncoPlex, a â¼2 Mb multi-gene NGS panel performed in the CLIA/CAP environment, was optimized for detecting cfDNA mutations. Tumor tissue and germline samples were sequenced for comparative analyses. Multivariate logistic regression was performed to determine the clinical characteristic associated with the successful detection of somatic cfDNA alterations (ie detection of at least one clearly somatic PC mutation). RESULTS: Plasma for cfDNA sequencing was obtained from 93 PC patients along with tumor tissue (N = 67) and germline (N = 93) controls. We included data from 76 patients (72 prostate adenocarcinoma; 4 variant histology PC) in the analysis. Somatic DNA aberrations were detected in 34 cfDNA samples from patients with prostate adenocarcinoma. High PSA level, high tumor volume, and castration-resistance were significantly associated with successful detection of somatic cfDNA alterations. Among samples with somatic mutations detected, the cfDNA assay detected 93/102 (91%) alterations found in tumor tissue, yielding a clustering-corrected sensitivity of 92% (95% confidence interval 88-97%). All germline pathogenic variants present in lymphocyte DNA were also detected in cfDNA (N = 12). Somatic mutations from cfDNA were detected in 30/33 (93%) instances when PSA was >10 ng/mL. CONCLUSIONS: Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens.
Assuntos
Adenocarcinoma/sangue , Adenocarcinoma/química , Biomarcadores Tumorais/análise , DNA Tumoral Circulante/análise , Neoplasias da Próstata/sangue , Neoplasias da Próstata/química , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Efeitos Psicossociais da Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Correct assessment of a genetic variant relies on the clinical context and knowledge of the underlying biology. We outline four scenarios encountered in genetic testing where careful consideration of the origin of genetic variation is required for variant interpretation.