New Brunswick, N.J. – January 3, 2019 – Investigators at Rutgers Cancer Institute of New Jersey have uncovered that some mutations detected with targeted genome sequencing of patients with solid tumors are a result of a group of hematologic malignancies known as myeloproliferative neoplasms (MPN). This discovery may have direct implications for treating cancer patients who may have a solid tumor as well as a MPN.

Rutgers Cancer Institute of New Jersey Associate Director for Translational Science and Chief of Molecular Oncology Shridar Ganesan, MD, PhD,  who is also an associate professor of medicine and pharmacology at Rutgers Robert Wood Johnson Medical School, and the Omar Boraie Chair in Genomic Science, along with Rutgers Cancer Institute researcher Hossein Khiabanian, PhD, assistant professor of pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School, are the senior authors on the work. Rutgers Cancer Institute investigator Gregory Riedlinger, MD, PhD, an assistant professor of pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School, is the lead author, and Mohammad Hadigol, PhD, a New Jersey Commission for Cancer Research postdoctoral fellow in the Khiabanian Lab, is a contributing author on this work. They share more about the research published in the January 3 online edition of JAMA Oncology (doi: 10.1001/jamaoncol.2018.6286):

Q:  Why is this topic important to explore?

A: Clinical sequencing assays are now routinely used to identify mutations in cancer for accurate diagnosis and treatment. Using these assays, the DNA from all cells within a specimen is sequenced, which include tumor cells as well as admixed stromal and blood cells. We previously reported that some mutations detected in targeted genome sequencing of patients with solid tumors arise from hematopoietic cells that infiltrate the tumor microenvironment. These mutations were due to an age-related condition known as clonal hematopoiesis of indeterminate potential or CHIP. However, since CHIP shares its mutational landscape with other hematologic diseases, it can confound distinguishing CHIP from malignancies such as MPN. MPNs frequently have a mutation in the JAK2 gene that alters the 617th amino acid residue from valine to phenylalanine. In this study, we sought to determine the cellular origin of JAK2-V617F in solid tumor sequencing and whether it was associated with a clinical diagnosis of a MPN. Recently published data attributed the detection of this mutation to the presence of CHIP, while others suggested that it arose in solid tumor cells.

Q:  How did you approach this work and what did you discover?

A: We analyzed clinical sequencing data from more than two thousand solid tumors tested at Rutgers Cancer Institute. Specimens from eight patients had JAK2-V617F mutations, but were present at abundances significantly different from that expected from tumor purity, suggesting they were either not present in all cancer cells or existed in a subset of non-cancer cells. Examination of clinical histories revealed that four of the eight patients had a diagnosis of a MPN while an additional patient had elevated platelet counts, which could indicate an unrecognized MPN. We performed manual macrodissection on paraffin-embedded specimens from three patients to enrich for solid tumor as well as hematopoietic cells and used highly sensitive sequencing and bioinformatics methods to detect mutations at very low abundances. In two of these patients with a diagnosis of MPN, the JAK2-V617F mutations were present in hematopoietic cells. In the third patient without prior diagnosis of MPN, we detected JAK2-V617F in the tumor cells. Interestingly, in one patient with MPN and in the one without MPN, we also detected CHIP-associated mutations in lymphocyte-enriched cell populations. Our study showed for the first time that JAK2-V617F identified in solid tumor sequencing can indicate a coexistent MPN with the mutation detected in infiltrating hematopoietic cells and not the solid tumor.  

Q:  What are the implications of these findings?

A: There have been conflicting reports in the literature as to whether JAK2-V617F mutations detected in solid tumor sequencing assays are the result of alterations in the solid tumor or CHIP. Our analysis shows that although both of these results are possible, detection of JAK2-V617F can instead be associated with a coexistent MPN. This is of importance since the management of patients with a MPN would be different than with a patient that has the JAK2-V617F from CHIP or the solid tumor. These findings complement our previous work on CHIP and highlight the need for proper interpretation of variants detected in clinical sequencing of tumor samples. Specifically, when MPN-associated mutations are observed in solid tumor sequencing, caution is necessary for proper patient management and a hematologic workup should be considered in the appropriate clinical context.

This research was supported by the Comprehensive Genomics, Biomedical Informatics, and Biospecimen Repository Shared Resources at Rutgers Cancer Institute of New Jersey (P30CA072720), the Rutgers Office of Advanced Research Computing (NIH 1S10OD012346-01A1), as well as pilot project funding from the Department of Pathology and Laboratory Medicine at Rutgers Robert Wood Johnson Medical School.