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. 2015 Nov 18:8:688.
doi: 10.1186/s13104-015-1675-x.

Focused molecular analysis of small cell lung cancer: feasibility in routine clinical practice

Fatma Abdelraouf  1   2 , Adam Sharp  3   4 , Manisha Maurya  5 , Debbie Mair  6 , Andrew Wotherspoon  7 , Alex Leary  8 , David Gonzalez de Castro  9 , Jaishree Bhosle  10 , Ayatallah Nassef  11   12 , Taghrid Gaafar  13   14 , Sanjay Popat  15   16 , Timothy A Yap  17   18 , Mary O'Brien  19
Affiliations

Focused molecular analysis of small cell lung cancer: feasibility in routine clinical practice

Fatma Abdelraouf et al. BMC Res Notes. .

Abstract

Background: There is an urgent need to identify molecular signatures in small cell lung cancer (SCLC) that may select patients who are likely to respond to molecularly targeted therapies. In this study, we investigate the feasibility of undertaking focused molecular analyses on routine diagnostic biopsies in patients with SCLC.

Methods: A series of histopathologically confirmed formalin-fixed, paraffin-embedded SCLC specimens were analysed for epidermal growth factor receptors (EGFR), KRAS, NRAS and BRAF mutations, ALK gene rearrangements and MET amplification. EGFR and KRAS mutation testing was evaluated using real time polymerase chain reaction (RT-PCR cobas(®)), BRAF and NRAS mutations using multiplex PCR and capillary electrophoresis-single strand conformation analysis, and ALK and MET aberrations with fluorescent in situ hybridization. All genetic aberrations detected were validated independently.

Results: A total of 105 patients diagnosed with SCLC between July 1990 and September 2006 were included. 60 (57 %) patients had suitable tumour tissue for molecular testing. 25 patients were successfully evaluated for all six pre-defined molecular aberrations. Eleven patients failed all molecular analysis. No mutations in EGFR, KRAS and NRAS were detected, and no ALK gene rearrangements or MET gene amplifications were identified. A V600E substitution in BRAF was detected in a Caucasian male smoker diagnosed with SCLC with squamoid and glandular features.

Conclusion: The paucity of patients with sufficient tumour tissue, quality of DNA extracted and low frequency of aberrations detected indicate that alternative molecular characterisation approaches are necessary, such as the use of circulating plasma DNA in patients with SCLC.

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Figures

Fig. 1
Fig. 1
Patient cohort. One hundred and five patients were diagnosed with SCLC between the 1st July 1990 and 1st September 2006. Thirty-three patients identified had no tissue blocks available and a further 12 patients had insufficient tissue for molecular analysis. Sixty patients with sufficient tissue for molecular analysis were included in the study
Fig. 2
Fig. 2
Positive BRAF mutation detected by capillary electrophoresis-single strand conformation analysis. Capillary electrophoresis-single strand conformation analysis demonstrates V600E BRAF mutation in patient sample. Positive and negative controls are shown. Black arrow corresponds to extra peak representing the V600E BRAF mutation
Fig. 3
Fig. 3
Proposed model for molecular analysis of SCLC and incorporation into translational studies. Patients should undergo a tumour biopsy to obtain sufficient tissue for molecular analysis alongside collection of blood specimens to isolate circulating plasma DNA (cpDNA) and circulating tumour cells (CTCs). Molecular analysis of these samples should be used for translational studies. These may be clinical studies in which patients identified to have actionable aberrations enter clinical studies in which there treatment (T) is determined by sequencing data. These patients should have sequential genomic analysis through cpDNA and CTCs to identify further molecular aberrations (X) that may confer resistance and determine further treatment (A, B, C and D) strategies. These molecular studies are also likely to identify novel or non-actionable changes within SCLC that should be further studied to determine their functional role and potential as novel therapeutic targets for the treatment of SCLC
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