Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM

Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM

IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer

Purpose: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. Methods: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. Results: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. Conclusions: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone

Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM