The Lynx Group

Whole Genome Sequencing Detects Chromosomal Aberrations Associated with Systemic Mastocytosis

Conference Correspondent

Systemic mastocytosis (SM) is a malignancy in which mast cells overproliferate and accumulate in various organs. Non-advanced forms of SM include indolent SM (ISM) and smoldering SM (SSM). ISM and SSM can progress to more aggressive advanced SM (AdvSM), which include aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast-cell leukemia (MCL). Although most patients with SM will test positive for mutations in the KIT tyrosine kinase gene, especially the D816V substitution, somatic mutations in other genes have also been identified as potential risk factors for AdvSM. However, methods of detecting chromosomal changes and genetic alterations in SM are lacking.

Whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) may be useful options to identify cytogenetic aberrations and mutations associated with SM. Whole genomic information has shown to be useful in identifying and characterizing mutations that drive cancer progression, whereas transcriptome data allow identification of possible biomarkers. Researchers compared WGS/WTS data from 120 patients with SM to KIT D816V polymerase chain reaction (PCR), targeted sequencing, and cytogenetic analyses. Of the patient cohort, 73 (60.8%) were diagnosed with ISM and 47 (39%) were diagnosed with AdvSM: SM-AHN (n = 43; 35.8%), ASM (n = 3; 2.5%), and MCL (n = 1; 0.8%).

The proportion of patients in whom KIT D816V was observed was variable according to method of detection: PCR (98%), WGS (21%), and WTS (46%). Changes identified by chromosome banding analysis were also observed with WGS/WTS analysis in all but 3 patients. Notably, WGS/WTS analysis identified 16 additional aberrations that were not recognized by chromosome banding. Chromosomal aberrations were observed with WGS at a higher rate in AdvSM (36%) compared with non-advanced SM (12%; P <.05). When WTS was applied, there was no difference in KIT D816V detection between AdvSM (45%) and ISM (47%). However, the KIT D816V detection rate by WGS was significantly higher in AdvSM (36%) compared with non-advanced SM (12%; P <.05). Non-KIT mutations were assessed among genes that are commonly associated with SM and were detected in 46% of patients with a median of 2 mutations. The occurrence of non-KIT mutations as well as the median number of mutations per patient was higher in AdvSM (83%) compared with non-advanced SM (22%; P <.05). Patients with both chromosomal aberrations and non-KIT gene mutations identified by WGS/WTS (n = 16), one type of aberration (n = 47; gene mutations only, n = 38; chromosomal aberrations only, n = 8), or no aberration but KIT D816V (n = 57), showed significant differences in overall survival (P <.05). The presence of both types of aberrations was associated with the lowest overall survival (approximately 7 years), while the absence of aberration was associated with greatest overall survival (approximately 30 years) and good prognosis for the patient.

Researchers conclude that PCR identified KIT D816V mutations in more patients compared with WGS/WTS, indicating the continued need for PCR informed diagnostic decisions. WGS/WTS detects chromosomal aberrations and non-KIT mutations in patients with SM at a higher rate than cytogenetic methods, and the absence of both aberrations as identified by WGS/WTS indicates non-advanced disease, which is associated with higher overall survival. These data support the role of WGS/WTS testing in SM diagnostic decision-making.

Hoermann G, Meggendorfer M, Baer C, et al. Whole genome sequencing identifies non-KIT mutations and cytogenetic aberrations in systemic mastocytosis but has limited sensitivity for detection of KIT D816V. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 1495.

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