Ressource pédagogique : Translational cancer genomics and proteomics

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Translational science : how to move from biology to clinical applications Evaluation of cell-free DNA (cfDNA) is a very attractive tool to serve as “liquid biopsy” to define and establish mutational changes in circulating tumor DNA (ctDNA) during cancer therapy. To identify tumor specific mutations in serum ctDNA associated with resistance against tamoxifen in metastatic breast cancer. Ten ER-positive metastatic breast cancer patients treated with first-line tamoxifen with blood sera available at start therapy (S1), during treatment (S2) and at disease progression (S3) were selected. DNA from normal and primary tumor tissue and cfDNA from sera were sequenced using the Ion Torrent Personal Genome Machine (Ion-PGM). In total 1,242 exons of 45 genes were sequenced up to 5,000 reads depth coverage and single nucleotide variants (SNVs) with at least 2% frequency were defined. Identified SNVs were re-sequenced for confirmation or checked by snapshot assays. The initial analyses revealed 246 SNVs in at least one serum sample, including 96 variants observed at disease progression in serum S3. The 96 variants contained 11 SNVs that were also present within the primary tumor in 6 patients. Re-sequencing at deeper level confirmed all 11 tumor SNVs. These variants occurred in 9 genes and were predicted pathogenic for CDH1, CREBBP, NF1, PIK3CA, SMAD4, and TP53. The variants for CDH1, CREBBP, and SMAD4 were not previously considered tumor-specific in publically available repositories. The remaining 85 variants at disease progression were only observed in serum, and covered 45 serum SNVs merely detected in serum S3 of above 6 patients. Of the 45 SNVs, 3 were already reported in cancer for BRCA1, MAP3K1 and PTCH1, with the first two SNVs considered pathogenic. Moreover, only one not yet reported SNV for AKAP9 (H562Q) was detected in all three sera but not in the tumor within one patient. Re-sequencing of these 4 serum SNVs confirmed only the AKAP9 variant, which is not known yet to be involved in tumor biology. Twelve variants occurring in 10 genes were identified and confirmed after re-sequencing in primary tumor DNA and serum taken at progression, which may be associated with tamoxifen therapy resistance and/or reflecting tumor load. Four of these SNVs have not been linked to to cancer before. Further studies are needed to explore the clinical relevance of the variants as tumor marker or a marker explaining tamoxifen resistance. Cette présentation a été donnée dans le cadre du Scientific BRIO Day 2 organisé annuellement par le SIRIC BRIO et qui a pour but de réunir tous les acteurs du SIRIC BRIO et plus largement de la cancérologie à Bordeaux.

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• Cancer (616.994)

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