Unraveling the multiple myeloma genome in the next-generation sequencing era: challenges to translating knowledge into the clinic

Abstract

The origin and progression of human cancers is caused by the acquisition of genetic and epigenetic alterations. Over the last decades, significant efforts and technological advances were key in the characterization of the cancer genome in a wide range of tumors. In 1976, Peter Nowell, following the observation of karyotypic heterogeneity in multiple tumor genomes, proposed a multistep process to explain the molecular basis of tumorigenesis [1]. This model was not only the first comprehensive ana lysis of genetic heterogeneity and instability in the tumor clone, but also led for the first time to the concept of personalized medicine, where therapy should be individualized according to the genetic background observed in the tumor clone. In the mid-1980s, at the time that the molecular techniques to search for oncogenes and tumor suppressor genes were developed, Renato Dulbecco pointed out in an influential article that sequencing the human genome was a critical priority, saying that the research community was faced with two options: either keep discovering the genes important in cancer individually, or use a massive approach and sequence the whole genome [2]. 4 years later, the Human Genome Project was started. The Human Genome Project required several years of collaborative work from worldwide leading sequencing institutes and a budget of US$300 million to sequence the first single genome with seven-times coverage [3]. Now, 10 years after the completion of the first draft of the Human Genome Project, the incorporation of the massively parallel sequencing (also known as nextgeneration sequencing) technologies has revolutionized the search for genetic alterations in tumor genomes. The simultaneous catalog of all mutations, copy number aberrations and structural abnormalities in an entire cancer genome can be performed in one week using a single sequencer and for only US$5000. With the ultimate goal of offering the test for US$1000 in the near future, the implementation of next-generation sequencing in clinical practice will soon be a reality.