Genome changes tracked during multiple myeloma initiation, progression and treatment
New findings shed light on cancer behaviorScientists have made significant progress toward elucidating key genetic events associated with the development and progression of multiple myeloma (MM), an incurable malignancy that is the second most common cancer of the blood. The results, published in the April issue of Cancer Cell, provide new genetic and biological insights that open innovative directions for the discovery of effective therapeutics that can be targeted to specific MM patients based on genetic perturbations known to contribute to MM pathogenesis.
Although genetic screening studies have provided some insight into the pathogenesis that underlies MM, the full landscape of genomic events driving cancer initiation, progression, and response to treatment have remained hidden from view. Drs. Ron A. DePinho from the Dana-Farber Cancer Institute, Cameron Brennan of Memorial Sloan-Kettering Cancer Center, and John Shaughnessy of the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences and their colleagues performed a high-resolution and integrated analysis of gene copy number alterations and expression profiles of outcome-annotated MM clinical specimens.
The researchers discovered a high level of molecular heterogeneity typified by many new recurrent amplifications and deletions that point to a large number of yet-to-be-discovered oncogenes and tumor suppressor genes. These amplification and deletion patterns define new disease subgroups of MM that are characterized by varied dysregulation of distinct cancer-relevant genes and can be correlated with different clinical outcomes. Importantly, several candidate genes identified in this study possess broad clinical and biological relevance, as they are also associated with histologically unrelated malignancies such as pancreatic, lung, breast, and ovarian cancer and may thus represent a rite of passage for many different cancers.
"This integrated and detailed view of the MM genome is consistent with the concept of widespread changes in the expression of genes with cancer activity in the pathogenesis of MM, a concept with therapeutic and diagnostic implication for MM in particular and cancer in general," explains Dr. DePinho. The researchers suggest that on a broader scale in relation to the human cancer genome project, their results will serve to direct costly sequencing efforts toward those specific regions that contain genes displaying high pathogenic relevance. "This story clearly indicates that we are dealing with the tip of the iceberg when it comes to the universe of cancer genes," says Dr. DePinho.
This work was supported in part by The Fund to Cure Myeloma in the Center for Applied Cancer Science, a new comprehensive cancer drug development initiative at Dana-Farber Cancer Institute, Harvard Medical School.
The researchers include Daniel R. Carrasco,1,2,8 Giovanni Tonon,1,8 Yongsheng Huang,3,8 Yunyu Zhang,1 Raktim Sinha,1 Bin Feng,1 James P. Stewart,3 Fenghuang Zhan,3 Deepak Khatry,1 Marina Protopopova,5 Alexei Protopopov,5 Kumar Sukhdeo,1 Ichiro Hanamura,3 Owen Stephens,3 Bart Barlogie,3 Kenneth C. Anderson,1,4 Lynda Chin,1,7 John D. Shaughnessy Jr.,3 Cameron Brennan,6, and Ronald A. DePinho1,5.
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
2 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115
3 The Donna and Donald Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
4 The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115
5 Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
6 Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, Department of Neurosurgery, Weill Cornell Medical College, New York, New York 10021
7 Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115
8 These authors contributed equally to this work.
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