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题目:: Gene expression profiles defining molecular subtypes, coupled with signatures of tumor biology and chemotherapy sensitivity provide a novel therapuetic approach to multiple myeloma.
作者:: Anguiano(A),Tuchman(S A),Perez(B),Salter(K H),Redman(R C),Zhan(F),Barlogie(B),Potti(A),Shaughnessy(J D)
状态:: 发布时间2016-12-12 , 更新时间 2016-12-12
期刊:: J Clin Oncol
摘要:: 8501 Gene expression profiles reflecting hyperploidy (HY) or specific genetic lesions leading to translocations, (including C-MAF, MAFB, CCND1, CCND3 and MMSET (MS)), have been used to define distinct phenotypes of multiple myeloma. That several of these subtypes are at higher risk of progression and death emphasizes the need for novel therapeutic strategies. Employing gene expression analysis in a cohort of 560 newly diagnosed multiple myeloma patients (training-352, validation-208) we applied expression signatures reflecting the deregulation of oncogenic signaling pathways (Myc, Ras, Src, B-catenin, E2F1 and PI3K), profiles representing an altered tumor microenvironment (chromosomal instability, angiogenesis, hypoxia and TNF-a) and signatures of chemotherapy sensitivity (melphalan, vincristine, adriamycin, cyclophosphamide, cisplatin and etoposide) to a training cohort patients previously enrolled in Total Therapy 2 (TT2). Distinct patterns of altered tumor biology and chemosensitivity between the molecular subtypes (CD1, CD2, LB, HY, MF, MS and PR) was observed. In particular, the low risk HY group (EFS 68% and OS 79% with 3 years median follow-up) demonstrated increased activation of Myc (p<0.0001) and PI3K (p=0.03) pathways when compared to the high risk MS group (EFS 31% and OS 51%). Alternatively, the MS group demonstrated increased evidence of chromosomal instability (p=0.0002). The HY group demonstrated increased sensitivity to vincristine (p=0.04) and adriamycin (p=0.003), while the MS group demonstrated increased sensitivity to cyclophosphamide (p<0.0001) and to cisplatin (p=0.02). Importantly, similar analysis in an independent validation set of 208 patients enrolled in the Total Therapy 3 (TT3) demonstrated the reproducibility of the patterns. This analysis has demonstrated distinct patterns of altered tumor biology and chemotherapy sensitivity amongst the clinically relevant subtypes of multiple myeloma. Additional results dissecting the molecular phenotypes of multiple myeloma will be presented. Genomic evidence of chemotherapy sensitivity and oncogenic pathway activation may provide an opportunity for selection of therapeutic modalities. No significant financial relationships to disclose.
语言:: eng
DOI:

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