Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary.
Adenocarcinoma
/ genetics
Adolescent
Adult
Carcinoma, Squamous Cell
/ genetics
Class I Phosphatidylinositol 3-Kinases
/ genetics
Cyclin-Dependent Kinase Inhibitor p16
/ genetics
DNA Copy Number Variations
/ genetics
Female
High-Throughput Nucleotide Sequencing
Humans
Male
Neoplasms, Unknown Primary
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Receptor, Fibroblast Growth Factor, Type 4
/ genetics
Receptor, Notch1
/ genetics
Tumor Suppressor Protein p53
/ genetics
Young Adult
cancer of unknown primary
mutational profiling
prognosis
targeted therapy
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
31
10
2019
revised:
08
01
2020
accepted:
09
01
2020
pubmed:
24
1
2020
medline:
8
1
2021
entrez:
24
1
2020
Statut:
ppublish
Résumé
Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno- and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin-fixed, paraffin-embedded tissues. For library preparation, mostly multiplex PCR-based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event-free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data.
Substances chimiques
CDKN2A protein, human
0
Cyclin-Dependent Kinase Inhibitor p16
0
KRAS protein, human
0
NOTCH1 protein, human
0
Receptor, Notch1
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
FGFR4 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 4
EC 2.7.10.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3053-3064Informations de copyright
© 2020 UICC.
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