79. Implications of fortuitous detection of JAK2 V617F mutations with solid tumor clinical sequencing

Aly Abdelkareem

Marie-France Gagnon

Marie-France Gagnon received her MD at the University of Montreal. Subsequently, she completed her Medicine residency and Hematology fellowship at the University of Montreal. She also holds a master’s degree in biomedical sciences focusing on the genetic determinants of hematopoiesis from this institution. She is currently training as a fellow in Laboratory Genetics and Genomics at Mayo Clinic.


Marie-France Gagnon, Teja Koganti, Beth Pitel, Katherine Geiersbach

Mayo Clinic, Rochester, MN, USA

Genomic profiling of tumor provides valuable diagnostic, prognostic and therapeutic information. However, as clinical sequencing often relies on tumor-only approaches, factors such as infiltration from cells of hematopoietic lineage may confound accurate inference of variants present in tumor. We sought to investigate the frequency of a hallmark mutation in myeloid malignancies, JAK2 V617F, in solid tumor samples subjected to genetic testing at our institution and whether these underlie coexistence of a hematologic malignancy. We tested 6571 tumor samples between 2018 and 2021 that were investigated with targeted sequencing analysis. Of these, 5 (0.07%) harbored a JAK2 V617F mutation, a frequency comparable to that reported in the cBioPortal database (74/76639, 0.1%). These included three cases of melanoma, one cutaneous squamous cell carcinoma and one colorectal adenocarcinoma occurring in patients aged 51 to 93 years. No case showed evidence of overt superimposed hematologic malignancy, yet scattered CD45-positive hematopoietic cells were documented. Four cases (80%) harbored additional BRAF, CDNK2A, TP53 and PTEN tumor-specific mutations. JAK2 V617F mutations tended to be present at lower allele frequencies than other mutations (respective means 0.09 and 0.29). Two cases with available clinical information were previously known for hematologic malignancies (polycythemia vera and systemic mastocytosis with associated polycythemia vera). Our study emphasizes the importance of maintaining vigilance to sources of misleading results with tumor-only testing such as potential for misattribution of variants from infiltrating leukocytes. Importantly, detection of JAK2 V617F mutations may indicate a concurrent myeloproliferative neoplasm and inclusion of this disclaimer in the report should be considered.