Role of genomic factors on late adverse events after lymphoma

Despite the increased cure rates of Hodgkin lymphoma (HL) and diffuse large B*
cell lymphoma (DLBCL), life expectancy remains compromised due to the
occurrence of late treatment-related complications, such as cardiovascular
disease and second malignant neoplasms. The risk of late adverse events can
only be partially explained by treatment-related factors and lifestyle,
suggesting a substantial genomic component. However, the genomic determinants
of late adverse events have not been comprehensively studied. We hypothesize
that genomic markers contribute to the risk of late adverse events and can be
used for risk stratification.

Our main objective is to dissect the genomic determinants of treatment-related
adverse events after lymphoma, specifically cardiovascular disease and second
malignant neoplasms. As such, we will assess the association of genetic and
epigenetic markers with the risk of late adverse events in 5-year survivors of
lymphoma. We will evaluate whether genomic signatures and polygenic risk scores
based on these markers can modulate and predict the risk of late adverse
events. In addition, we will evaluate to what extent genomic determinants are
shared across different types of late adverse events and assess the role of
genomic markers identified in the general population. In an optional part of
the study, we will also assess the molecular profile of therapy-induced second
malignancies.

This observational study will be performed in a well-defined cohort of 5-year
survivors of HL and DLBCL identified through the BETER consortium.

5-year survivors of HL or DLBCL who were identified through the BETER
consortium will be invited to participate in this study. Living survivors will
be approached and invited by their treating physician at the BETER survivorship
clinic, or, when they do not visit a BETER survivorship clinic, by their former
treating physician at the participating BETER clinic. Biospecimens of deceased
survivors will be collected through the national pathology registry (PALGA). In
total, we plan to include 8,000 survivors in our study.

With the results of our study, we will advance the knowledge about the
susceptibility to late adverse events after lymphoma and the underlying
pathophysiology. In addition, identified genomic risk factors can inform
personalized treatment of future lymphoma patients and benefit personalized
screening of current lymphoma survivors for adverse events. The burden is
considered low: it is an observational study with a single blood draw (and a
health questionnaire for survivors who do not undergo screening).