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Detection of JAK2 V617F mutations linked to myeloproliferative neoplasms

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January 30, 2019

JAK2 V617F mutations detected by solid tumor sequencing appeared associated with coexistent myeloproliferative neoplasms, according to a research letter published in JAMA Oncology.

 “Recent studies have shown that certain mutations identified in sequencing assays did not reflect alterations in the tumor but instead revealed alterations in infiltrating hemopoietic cells, possibly from undiagnosed clonal hematopoiesis of indeterminate potential (CHIP), an age-related expression of hematopoietic stem cells harboring somatic mutations, predominantly in DNMT3A, TET2 and ASXL1,” Gregory Riedlinger, MD, PhD, assistant professor of pathology in the division of translational pathology at Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, and colleagues wrote. “Mutations in other genes associated with hematologic diseases are detected less frequently in CHIP and, when these mutations are encountered, reports have attributed them to either the tumor or CHIP.”

Riedlinger and colleagues assessed clinical sequencing data on 2,030 solid tumors examined at Rutgers University-New Brunswick between Nov. 1, 2012, and Aug. 31, 2018.

Researchers observed JAK2 V617F mutations in specimens from eight patients (median age, 74 years; range, 60-82; five men), but closer examination revealed that mutations existed at variant allele frequencies (VAFs) that differed significantly from those anticipated with tumor purity. Further analysis — including manual macrodissection of paraffin-embedded specimens to enrich for cancer or hematopoietic cells, high-depth sequencing with a 49-gene panel, and testing against 33 sequenced JAK2 wild-type samples — validated the existence of JAK2 mutations in hematopoietic elements.

The researchers assessed patients’ clinical histories and found half (n = 4) of those with JAK2 V618F mutations identified on solid tumor sequencing had been diagnosed with myeloproliferative neoplasms. Two of the patients had a diagnosis of polycythemia vera, one had essential thrombocythemia, and one had myelofibrosis.

One patient had a platelet count of 529 x 109 µL prior to starting chemotherapy. Concomitant chemotherapy confounded the results of blood tests for the other three patients not diagnosed with myeloproliferative neoplasms. 

The validation analysis of the macrodissected specimens showed that two of the three patients had JAK2 V617F in lymphocyte-enriched samples at VAFs that were significantly higher (5.6% at 2,807x and 28.1% at 3,029x) than in tumor enriched samples (3.5% at 3,264x and 5.9% at 1,772x; P < .001 for all). Among these individuals, tumor-specific mutations were all detected at significantly higher VAFs in tumor-enriched samples.

CHIP-associated mutations in U2AF1 and TET2 were detected in one patient at significantly higher VAFs in the lymphocyte-enriched sample. Results in another patient with no previous myeloproliferative neoplasm diagnosis showed detection of JAK2 V61F at a significantly higher VAF in the tumor-enriched sample (12% at 1,788x vs, 2.2% at 2,757x). A CHIP-associated mutation in DNMT3A in this patient was detected at a significantly higher VAF in the lymphocyte-enriched sample. This indicated that JAK2 V617F likely existed in tumor cells.

“There have been conflicting reports in the literature as to whether JAK2 V617F detected by solid tumor sequencing is associated with a mutation in the tumor or CHIP,” the researchers wrote. “Our analysis suggests that although both of these results are possible, detection of JAK2 V617F may instead be associated with a coexistent myeloproliferative neoplasm. Limitations may arise in distinguishing underlying JAK2 V617F mutations from CHIP vs. those from an myeloproliferative neoplasm in patients receiving chemotherapy for their solid tumors.” – by Jennifer Byrne

Disclosures: Riedlinger reports consultant and scientific advisory board roles with Personal Genome Diagnostics. Please see the study for all other authors’ relevant financial disclosures.

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itj+ Perspective

Aaron Gerds, MD, MS

With the cold winter air comes Super Bowl season, and the gatherings celebrating the gladiators of the gridiron are sure to feature some unhealthily good dips — just cause to break nascent new year’s resolutions. I may hold out at first but, as the evening wears on, I always give in to the gastronomic siren’s call. Upon first bite, crunchy irregularities in an otherwise perfectly smooth union of onion, spice and dairy throw me off. CHIPs in the dip. Are these carb-rich fragments potato or corn based? Were they intentionally placed there by the chef or an accidental consequence of a stream of previous partygoers snacking? Should I just stick to the cheese plate?

Like the fragments in an otherwise smooth dip, detection of myeloid neoplasia-related mutations pop up by surprise and can raise more questions than provide answers. Whether it is discovered in a breast tumor biopsy or in bone marrow of a patient with a plasma cell disorder, the main challenge is determining whether the mutation represents a true myeloid neoplasia or CHIP (clonal hematopoiesis of indeterminant potential). 

As demonstrated by Riedlinger and colleagues, a thorough clinical evaluation as well as variant allele frequency can help sort this out. Knowing about the coexistence of a clonal hematopoietic process can be powerful information.

Targeting a mutation thought to be in the primary tumor but actually in the hematopoietic clone would dramatically affect efficacy. Also, consideration may be given to limiting exposure to genotoxic chemotherapy when formulating a treatment plan for the primary malignancy. 

Although clonal hematopoiesis or CHIP may be an uninvited party guest, its presence can’t be ignored completely.

Aaron T. Gerds, MD, MS

HemOnc Today Next Gen Innovator
Cleveland Clinic

Disclosure: Gerds reports advisory board roles with Apexx Oncology and Celgene, as well as research support from Celgene, CTI Biopharma, Imago BioSciences, Incyte, Roche and Samus Therapeutics.