Understanding Sequence-Specific Oncogenic Mutations in Cancer
Whole-genome analyses have now produced near-comprehensive topographies of gene mutations for certain human cancers, enabling both detailed molecular studies of cancer pathogenesis and potential of precisely targeted therapies. For certain childhood and adult cancers, recent studies have begun to reveal the essential functions of non-coding mutations that can induce aberrant expression of cellular proto-oncogenes. In many instances, these mutations appear to be site or sequence-specific and caused by endogenous mutagens, such as RAG1/2 recombinase, APOBEC deaminase, and LINE and Alu transposons. In addition, distinct mutational classes have been observed in a large fraction of human cancers, but their causes remain currently undefined. The existence of site-specific and endogenous oncogenic mutagens implies the existence of distinct mechanisms of cancer pathogenesis, with direct implications for treatment, diagnosis, and prevention. This workshop will bring together experts in genome sequence analysis, molecular and cellular cancer biology, and translational investigation. This is expected to lead to deeper insights and enhance collaboration of fundamental causes of cancer pathogenesis.
Workshop on interactions between the microbiome and immune system in the lymphodepleted host.
Hematopoietic stem cell transplantation is characterized by significant changes in the intestinal microbiome as well as delayed immune recovery, which is accentuated in patients receiving an allograft, either due to graft-versus-host disease and its treatment or T cell depletion used to prevent it. With the advent of next generation sequencing, we have gained new insights into both the microbiome and immune system in the transplant patient. Investigators at MSKCC have been at the forefront of many of these advances, showing relationships between microbiome composition and post-transplant survival and relapse, as well as a relationship between immune recovery and survival and identifying factors that drive immune recovery. Furthermore, recent studies in solid tumor patients have demonstrated interactions between the intestinal microbiome and responses to checkpoint inhibitors.
Integrating our knowledge of these two complex systems and understanding how they interact could have the potential to not only improve outcomes in transplant patients but also other patients rendered lymphopenic through cytotoxic therapies for cancer. Drs. Miguel Perales (MSKCC), Robert Jenq (former MSKCC, now MDACC) and Eric Pamer (MSKCC) are planning a one day workshop that will bring together local and national experts in the field, including non-transplant experts, to increase our knowledge and define new avenues for research and collaboration. An immediate deliverable expected from the meeting is to formalize the design of a multicenter prospective biospecimen study in 1,000 transplant recipients proposed by Dr. Perales and which is under consideration in concept form by the Blood and Marrow Transplantation Clinical Trials Network.
Omar Abdel Wahab
Workshop on Understanding Spliceosome Mutations in Cancer
Over the last 10 years, great progress has been made in identifying the genetic alterations present in patients with cancer. One of the most surprising findings from this effort has been the discovery of frequent mutations in the machinery that splices RNA molecules in cancer cells. These so-called “spliceosomal mutations” are among the most common mutations in a variety of blood cancers but are also mutated across a variety of cancer types including lung cancer and breast cancer. Initial work has identified that these mutations actually drive the formation of cancers. Further efforts to understand these alterations is expected to identify opportunities to develop new therapeutics that are effective for cancers caused by these splicing factor mutations.
Understanding the role of the altered spliceosome in cancer will require inter-disciplinary collaboration among RNA biochemists, bioinformaticians, cancer biologists, and translational clinical researches. Recognizing this need, Drs. Harold Varmus (NCI/Weill Cornell College of Medicine), Siddhartha Mukkherjee (Columbia University), and Omar Abdel-Wahab (MSKCC) are organizing a 1-day workshop to bring together experts investigating this question. This will include investigators from a variety of fields to facilitate deeper collaboration and advances in this new avenue of cancer research.