Genetics in lymphomagenesis

Next-generation sequencing (NGS) technologies have played an essential role in defining the somatic genomic landscape of lymphomas, with most characterized by a considerable heterogeneity and the lack of a pathognomonic genomic event. From the host perspective, there is strong evidence for familial aggregation across lymphoma subtypes, and this does not appear to be confounded by nongenetic factors, supporting a shared genetic etiology across subtypes. However, a family history of a specific lymphoma subtype is also generally most strongly associated with risk for that specific lymphoma, supporting etiologic heterogeneity. While no major genes have been identified for lymphomas, genome-wide association studies (GWAS) have identified over 60 common (minor allele frequency > 5%) risk loci, nearly all are associated with specific subtypes. Host genetics has long been hypothesized to influence treatment response, toxicity, and prognosis, but current studies are limited. Ongoing challenges in the “post-genomic” era relate to the functional validation of the large number of mutated genes in the tumor and GWAS loci in the germline, in order to dissect their role in lymphomagenesis. While the use of somatic and host genomics for precision diagnosis, treatment, and prevention remains very promising, additional discovery and translational research will be needed before widespread adoption in the clinic.