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Sharzad Moghadam



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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.08 - Characterisation of Tumor Aetiology Using Mutational Signatures from the Non-Small Cell Lung Cancer Genome (Now Available) (ID 2667)

      14:30 - 16:00  |  Author(s): Sharzad Moghadam

      • Abstract
      • Presentation
      • Slides

      Background

      Somatic genome and exome analyses in cancer are currently dominated by a search for actionable mutations that inform new treatments for stage IV patients. Tumour mutational signatures, originally described by the Sanger centre, offer the potential to understand cancer cure and prevention strategies by using the genome/exome to define aetiological contributions to cancer from both environmental and endogenous sources.

      Method

      132 NSCLC samples were resected from 131 Greater Manchester patients and submitted to the UK 100,000 Genomes Project (Genomics England). A 5×5×5 mm fresh tumour sample was taken from the surgical specimen and stored at -80°C before undergoing genomic testing. To determine the neoplastic cell count, an additional tumour biopsy was taken for routine histological assessment. Germline DNA for comparable whole genome analysis was extracted from peripheral blood lymphocytes from a paired whole blood sample.Whole genome sequencing (WGS) was performed on tumor specimens and matched blood samples. Through the 100,000 Genomes Project pipeline, coverage was calculated from high-quality, non-overlapping bases present on well-mapped reads, as defined by SAMtools v1.1. Whole genome sequencing analysis was undertaken with the Illumina North Star pipeline v2.6.53.23. Data were then mined for tumour mutational burden (TMB) and mutational signature profiles. Signatures were extracted if they accounted for >5% of the mutations per sample. Clinical characteristics including tumor size, nodal status and stage were documented. Mann-Whitney and Fisher’s exact tests were used for statistical comparisons.

      Result

      Signature 8 (unknown aetiology) was the most prevalent mutational process overall (122/132 samples, 92.4%), while smoking signature 4 was the main mutational process in 86/131 (65.6%) of NSCLC cases. SIgnature 4 contributed as a principal or secondary mutational process to a total of 105/131 (80.2%) cancers; 104/105 (99%) of these patients were annotated as smokers or ex-smokers. Signature 5 (unknown aetiology) was the second most common driving signature (24/131, 18.3% cancers), contributing to an additional 19 cancers as a secondary mutational process (43/131, 32.8% of cancers overall). Median number of signatures contributing to signature 4 NSCLC was four, whilst non-smoking mediated NSCLC had contributions from a median of 5.5 mutational signatures (range 2-8). A median of four signatures contributed to both adenocarcinomas and squamous cancers, with 61/88 (69.3%) adenocarcinomas and 25/41 (61%) squamous cancers associated with signature 4 as their main mutational process. More results will follow on duration of signature 4 persistence following discontinuation of smoking, as well as prevalence of each signature according to common molecular subtypes of NSCLC.

      Conclusion

      Tumor mutational signatures have the potential to inform cancer prevention by offering a new level of genetic detail that reflects environmental and endogenous carcinogenesis. As expected, signature 4 offers the main contribution to NSCLC although a number of other aetiological factors are involved in its carcinogenesis. In particular, signatures 5 and 8, both currently of unknown aetiology, significantly contribute to the NSCLC genome. Along with that reported by the Sanger centre, this work lays the foundations for characterisation and identification of new carcinogens.

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