TY - JOUR
T1 - Next generation sequencing of carcinoma of unknown primary reveals novel combinatorial strategies in a heterogeneous mutational landscape
AU - Subbiah, Ishwaria M.
AU - Tsimberidou, Apostolia
AU - Subbiah, Vivek
AU - Janku, Filip
AU - Roy-Chowdhuri, Sinchita
AU - Hong, David S.
N1 - Funding Information:
Financial support provided by NIH/NCI under award number P30CA016672 Cancer Center Support Grant (CCSG).
Publisher Copyright:
© Subbiah et al.
PY - 2017
Y1 - 2017
N2 - Background: Advanced carcinoma of unknown primary (CUP) has limited effective therapeutic options given the phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conducted an exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified patients in our phase I clinic where archival tissue was available for a targeted NGS CLIA-certified assay. Results: Of 17 patients tested, 15 (88%) demonstrated genomic alterations (median 2 aberrations; range 0–8, total 59 alterations). Nine (53%) patients had altered cell signaling including the PI3K/AKT/MTOR (n=5, 29%) and MAPK pathways (n=3,18%); 7 (41%) patients demonstrated ≥1 alterations in tumor suppressor genes (TP53 in 5 patients), 8 (47%) had impaired epigenetic regulation and DNA methyla-tion, 8 (47%) had aberrant cell cycle regulation, commonly in the cyclin dependent kinases. Ten (59%) patients had alterations in transcriptional regulators. Concurrent mutations affecting cell cycle regulation were noted to occur with aberrant epigenetic regulation (n=6, 35%) and MAPK/PI3K pathway (n=5, 29%). Conclusion: Every patient had a unique molecular profile with no two patients demonstrating an identical panel of mutations. We identify two emerging novel combinatorial strategies targeting impaired cell cycle arrest, first with epigenetic modifiers and, second, with MAPK/PI3K pathway inhibition.
AB - Background: Advanced carcinoma of unknown primary (CUP) has limited effective therapeutic options given the phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conducted an exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified patients in our phase I clinic where archival tissue was available for a targeted NGS CLIA-certified assay. Results: Of 17 patients tested, 15 (88%) demonstrated genomic alterations (median 2 aberrations; range 0–8, total 59 alterations). Nine (53%) patients had altered cell signaling including the PI3K/AKT/MTOR (n=5, 29%) and MAPK pathways (n=3,18%); 7 (41%) patients demonstrated ≥1 alterations in tumor suppressor genes (TP53 in 5 patients), 8 (47%) had impaired epigenetic regulation and DNA methyla-tion, 8 (47%) had aberrant cell cycle regulation, commonly in the cyclin dependent kinases. Ten (59%) patients had alterations in transcriptional regulators. Concurrent mutations affecting cell cycle regulation were noted to occur with aberrant epigenetic regulation (n=6, 35%) and MAPK/PI3K pathway (n=5, 29%). Conclusion: Every patient had a unique molecular profile with no two patients demonstrating an identical panel of mutations. We identify two emerging novel combinatorial strategies targeting impaired cell cycle arrest, first with epigenetic modifiers and, second, with MAPK/PI3K pathway inhibition.
KW - Carcinoma of unknown primary
KW - Next generation sequencing
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M3 - Article
AN - SCOPUS:85022327450
SN - 2331-4737
VL - 4
SP - 47
EP - 56
JO - Oncoscience
JF - Oncoscience
IS - 5-6
ER -