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Marco Mora



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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.03-28 - Whole Exome Sequencing to Discover Lung Tumor Predisposition in Women with Previous Breast Cancer (ID 13033)

      16:45 - 18:00  |  Author(s): Marco Mora

      • Abstract

      Background

      During their life, women treated for breast cancer (BC) are at risk to develop lung cancer (LC); this risk is increased in smokers and if adjuvant radiation (aRT) was administered for BC. The relative risk of LC after treated BC ranges from 1.38 to 5.05. We hypothesized that genetic variants might predispose patients (Pts) to develop LC after BC. Our aim was to perform whole exome sequencing (WES) to identify genes associated with such predisposition.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      28 women who developed LC after BC (Study Population, SP) and 32 women treated for BC and with no secondary cancer after a follow-up ≥10 years (control population; CP) were enrolled. DNA was extracted from tumors and normal tissue samples from both SP and CP. Libraries were prepared with Agilent SureSelect All Exon kit and sequenced on Illumina HiSeq2500. Variant calling was performed with FreeBayes software.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age of SP at BC diagnosis was 63.5 years (range: 47-76); the median interval between diagnosis of BC and occurrence of LC was 4.5 years (range: 0-11). 13 Pts (46%) were never-smokers and, among the 21 Pts who had received aRT, 13 (62%) developed ipsilateral LC. At somatic analysis, no common mutation among known driver genes was shared between each BC and LC pair. WES performed on BC and LC samples identified two mutational signatures (S1 and S2). S1 (C>T substitutions) was observed in all BC samples and 16/28 (57%) LC samples and was more frequent in never-smokers (11 vs. 5 Pts) and among Pts who developed ipsilateral LC after aRT (10 vs. 6 Pts). S2 (C>A transversions) was observed in 12/28 LC samples (43%) and was strongly associated with smoking habit (10 vs. 2 Pts). When compared to COSMIC libraries, S2 resulted similar to COSMIC 4, common in LC samples collected from smokers. Since S1 was largely shared between paired BC and LC samples, we explored the eventuality of a genetic predisposition to S1-related malignancies with a gene-based burden test over rare germline variants in normal tissue of S1-LC Pts compared to CP Pts; 249 candidate genes were identified (FDR<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data identify two mutational S underlying the LC development. Germline analysis suggests that genetic variants may contribute to increase the risk of LC after BC.

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