Genetic characterisation of molecular targets in carcinoma of unknown primary

B Clynick,N T Harvey,C Saunders,K Meehan,G Sterrett,B Dessauvagie,R J N Allcock,W Erber

doi:10.1186/s12967-018-1564-x

Abstract

BackgroundCarcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions.MethodsCarcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations.ResultsVariants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1).ConclusionTaken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

Highlights

Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour
Many genomic studies are limited by the availability of poor quality formalin-fixed paraffin-embedded (FFPE) tissue which make up the main source of sample preparation and storage in routine diagnostics [10, 11]
Tumours were classified into four histological subgroups: squamous cell carcinoma (SCC; 38%), poorly differentiated (PD) carcinoma (29%), adenocarcinoma (24%), and neuroendocrine carcinoma (9%)

Summary

Introduction

Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Carcinoma of unknown primary (CUP) is classified as any type of metastatic epithelial tumour where, following extensive clinical history, physical examination, radiological studies and histopathological (including immunohistochemical) investigations, no primary site can be identified [1]. Clynick et al J Transl Med (2018) 16:185 the use of next-generation sequencing (NGS) technologies offers such an opportunity based on the identification of targeted therapies [9]. For NGS to be useful in the clinical setting, small amounts of FFPE tissue from variable sources needs to be successfully evaluated. With advancements in knowledge about important targetable mutations across various cancers, targeted sequencing approaches allow selective screening of known druggable targets using relatively small amounts of DNA input. Focusing on specific regions of interest through targeted sequencing leads to a greater depth of coverage, increasing the confidence of identifying low-level variants in cancer samples [10, 12]

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