Molecular driver alterations and their clinical relevance in cancer of unknown primary site.
Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
Harald
H
Löffler
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Institute of Pathology, Technische Universität München, Munich, Germany.
Nicole
N
Pfarr
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Mark
M
Kriegsmann
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Volker
V
Endris
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Thomas
T
Hielscher
Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Philipp
P
Lohneis
Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany.
Gunnar
G
Folprecht
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital/Harvard Medical School, Boston, USA.
Albrecht
A
Stenzinger
Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Manfred
M
Dietel
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Institute of Pathology, Technische Universität München, Munich, Germany.|National Center of Tumor Diseases (NCT), Heidelberg, Germany.|Member of the German Cancer Consortium (DKTK), Heidelberg, Germany.
Wilko
W
Weichert
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany.|Member of the German Cancer Consortium (DKTK), Heidelberg, Germany.
Alwin
A
Krämer
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)
CUP; carcinoma of unknown primary; driver mutations; massive parallel sequencing; p53