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E. Hovig



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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.07 - Higher frequency of genetic aberrations in KRAS- than in EGFR-mutated NSCLCs. A next-generation sequencing study on 96 samples. (ID 1094)

      16:55 - 17:00  |  Author(s): E. Hovig

      • Abstract
      • Presentation
      • Slides

      Background
      Genetic subtyping is increasingly being clinically relevant in NSCLC, and the search for novel targetable driver mutations is warranted. We intended to study the frequency and types of a vast number of potential druggable genetic aberrations in a large cohort of non-small cell lung cancers of all major histological subtypes. Herein we report the first findings.

      Methods
      Blood samples and tumor tissue was obtained from 96 operated early stage lung cancer patients admitted to Oslo University Hospital-Rikshospitalet in the period 2006-2011. Tissue was taken from the excised tumours, snap frozen in liquid nitrogen in the operation room, and stored at -80[o]C until DNA isolation. The tumor cell content in the specimens was found to be more than 70% in most samples. DNA was isolated from both tumor and corresponding blood sample according to standard procedures. High-throughput sequencing was performed using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes that target 3.2 Mb of the human genome and include exons for all known kinases, select cancer-specific genes and their associated UTRs, in total 612 genes. The derived sequence reads were analyzed based on a pipeline including calling variations, somatic mutations, DNA copy number changes, indels and genomic rearrangements, as well as functional annotations.

      Results
      Tissues from 48 females and 48 males were analyzed; 73 adenocarcinomas, 21 squamous cell carcinomas and 2 large cell carcinomas. 55 patients were in stage I, 27 in II and 14 in stage III. 13 patients were never-smokers. 25 samples harbored a KRAS-mutation and 10 an EGFR mutation. The number of mutated genes per sample varied from 1 to 81. The median number of mutated genes was 14 in the overall cohort, 15 in the EGFR wildtype/KRAS wildtype tumors, 17 in KRAS- mutated patients, 5 in the EGFR-mutated group and 6 in the never-smoking patients (of whom 4 patients were EGFR-mutated).Figure 1

      Conclusion
      KRAS-mutated tumors contain the same amount of genetic aberrations as in wild-type tumors, whereas EGFR-mutated tumors show a much lower number of mutations per tumor. Never-smokers harbor a low number of mutations independent of EGFR-mutation status. Novel driver mutations are probably found in samples with low numbers of mutations.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-011 - Next generation sequencing in lung cancers - focusing on the kinome (ID 1224)

      09:30 - 09:30  |  Author(s): E. Hovig

      • Abstract

      Background
      The majority of newly diagnosed patients with lung cancer are at an advanced stage, implying small chances of cure. However, lung cancer treatment has in the last years taken advantage of newly developed targeted therapies. EGFR-mutations and ALK-translocations are druggable alterations used in treatment decisions. There are several additional druggable mutations in cancers, specially among kinases, but their frequency in lung cancer is not fully elucidated.

      Methods
      Blood samples and tumour tissue were obtained from 96 operated early stage lung cancer patients admitted to Oslo University Hospital-Rikshospitalet in the period 2006-2011. 48 were women, 21 squamous cell carcinomas, 73 adenocarcinomas and two large cell carcinomas. Tissue was taken from the excised tumours, snap frozen in liquid nitrogen in the operation room, and stored at -80[o]C until DNA isolation. The tumour cell content in the specimens was found to be more than 70% in most samples. DNA was isolated from both tumour and corresponding blood sample according to standard procedures. Targeted resequencing was performed using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons for all known kinases, and selected cancer related genes and their associated UTRs, in total 612 genes. Targeted regions were sequenced at 50-60x coverage, allowing the detection of subpopulations down to 20%. The derived sequence was analysed based on a pipeline including calling variations, somatic mutations, DNA copy number changes, indels and genomic rearrangements, as well as functional annotations.

      Results
      There were significant differences in the number of somatic mutations detected within each tumour, ranging from 1 to 81, with a median of 14 mutations. Each mutation was supported by at least 20% mutant reads in the tumour, and the great majority corresponded to missense mutations. Over 1000 mutations were identified among all the samples analysed, but recurrent mutations were identified in specific pathways like the PI3K- and CHEK2-pathways. The TP53-gene was the most frequent mutated gene, in almost 50% of the samples, and these mutations have been validated by Sanger sequencing. Of the samples with more than 30 mutations, 55% revealed a mutation in the ATM-gene, whereas the frequency among the other samples was 14%, indicating a deregulation in DNA repair. Using the exon data from tumour and normal samples, we estimated DNA copy number changes, detecting gains and amplifications in cancer relevant genes i.e. KIT, ERK, EGFR.

      Conclusion
      In this pilot study, we have analysed 96 lung carcinomas by next generation sequencing, focusing on the kinome. We have identified several interesting mutational events, and analyses on different clinical subgroups are ongoing.