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• W2898097641 abstract "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. 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. 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). 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." @default.
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• W2898097641 date "2018-10-01" @default.
• W2898097641 modified "2023-10-18" @default.
• W2898097641 title "P2.03-28 Whole Exome Sequencing to Discover Lung Tumor Predisposition in Women with Previous Breast Cancer" @default.
• W2898097641 doi "https://doi.org/10.1016/j.jtho.2018.08.1215" @default.
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