A host of novel genetic variants have been implicated in individual predisposition for Hodgkin lymphoma (HL), according to a paper published in Blood.
Notably, the distribution of cases among those in younger age groups suggests a genetic predisposition for the disease, although age, sex, socioeconomic status, family size, and living in a westernized country are each associated with HL incidence. The degree to which genetic predisposition vs environmental factors plays a role in the disease’s pathogenesis is, however, not fully known.
Whole genome sequencing has previously suggested that some coding and noncoding variants may be implicated in HL etiology. For this study, researchers conducted WGS on 36 pedigrees where at least 2 individuals had been diagnosed with HL to identify genetic signatures associated with disease occurrence. All pedigrees also had 1 individual who had been diagnosed at 21 years old or younger.
The authors, who conducted this project at St Jude Children’s Research Hospital in Memphis, Tennessee, developed a tiered variant prioritization algorithm to identify genetic variants in the study population. Overall, the algorithm noted 44 variants likely to present a risk for HL in 28 pedigrees; 33 of the variants were coding and 11 were noncoding.
The 4 risk variants that were repeatedly noted were a coding variant in KDR, a region variant in KLHDC8B, a noncoding variant in a PAX5 intron, and a noncoding variant in a GATA3 intron. Novel risk variants included PAX5, GATA3, IRF7, EEF2KMT, and POLR1E.
“Identification of genetic predisposition variants for the development of HL may lead to novel therapeutic targets, better treatment of this rare disease, and addition of these genes to clinical germline genetic testing panels to facilitate early detection of symptoms, inform genetic counseling, and help determine risk for other family members,” the authors wrote in their report.
Flerlage JE, Myers JR, Maciaszek JL, et al. Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma. Blood. 2023;141(11):1293-1307. doi:10.1182/blood.2022016056