Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

TitleCollision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.
Publication TypeJournal Article
Year of Publication2022
AuthorsFontugne J, Cai PY, Alnajar H, Bhinder B, Park K, Ye H, Beg S, Sailer V, Siddiqui J, Blattner-Johnson M, Croyle JA, Noorzad Z, Calagua C, MacDonald TY, Axcrona U, Bogaard M, Axcrona K, Scherr DS, Sanda MG, Johannessen B, Chinnaiyan AM, Elemento O, Skotheim RI, Rubin MA, Barbieri CE, Mosquera JMiguel
JournalJCI Insight
Date Published2022 Feb 22
KeywordsBiomarkers, Tumor, DNA Mutational Analysis, Gene Rearrangement, Humans, Immunohistochemistry, Male, Mutation, Nuclear Proteins, Prostatic Neoplasms, PTEN Phosphohydrolase, Repressor Proteins, Retrospective Studies, RNA, Neoplasm, Trypsin Inhibitor, Kazal Pancreatic, Tumor Cells, Cultured, Tumor Suppressor Proteins

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Alternate JournalJCI Insight
PubMed ID35050902
PubMed Central IDPMC8876549
Grant ListP50 CA211024 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
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