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Methylation Shifts Identified in Relapsed Lymphoma Tumors

NEW YORK (GenomeWeb) – A team from the US and Italy has started characterizing the methylation changes that mark diffuse large B-cell lymphoma (DLBCL) tumors in patients experiencing relapse, uncovering clues that may eventually help in predicting or treating forms of the disease that recur after treatment.

As they reported in Nature Communications today, the researchers took a bisulfite sequencing-based look at methylation patterns in 13 matched tumor sets taken from 11 individuals with DLBCL at diagnosis and at relapse. Their results revealed pronounced epigenetic changes following treatment, though the number and type of differentially methylated regions in diagnostic and relapse tumors varied between individuals.

"The tumor after chemotherapy is not the same as the tumor before treatment," co-author Giorgio Inghirami, a researcher affiliated with Weill Cornell Medical College and the University of Torino, said in a statement. "This why it is so critical to have biopsies before any treatment of either primary as well as of relapsed lesions."

Along with potential treatment implications, the findings suggest methylation profiling at the time of diagnosis may also be informative, he and his colleagues explained. In follow-up experiments, they saw less varied tumor methylation at diagnosis in those who dodged relapse. In contrast, methylation heterogeneity was typically higher in diagnostic tumors from individuals who did go on to relapse.

"By studying more samples, it may ultimately be possible to scan the most informative regions of the epigenome of a patient's lymphoma at diagnosis to predict whether treatment will be successful and whether the cancer may recur," Weill Cornell pathology and laboratory medicine researcher Wayne Tam, a co-author on the study, said in a statement.

For the first stage of their study, the researchers used enhanced, reduced representation bisulfite sequencing to assess methylation levels at 3 or 4 million sites where cytosine neighbors guanine in the genome, testing banked biopsy samples from 11 chemotherapy-treated DLBCL patients who relapsed some six months to 13 years after treatment.

The matched sample pairs for each individual included diagnostic tumors that had not been treated and tumor samples collected from one or more sites in the body after treatment and relapse.

Comparisons of each diagnostic-relapse tumor pair revealed methylation changes at tens of thousands to more than 1 million sites per sample, including regions showing enhanced or — more frequently — diminished methylation at relapse.

While the nature and trajectory of these shifts varied from one patient to the next, the team saw an over-representation of relapse-related methylation alterations to components of a pathway containing the transforming growth factor-beta, or TGF-beta.

The results pointed to a decline in intra-tumor methylation heterogeneity at relapse, though heterogeneity in the diagnostic tumors appeared to herald relapse risk: The researchers detected higher levels of intra-tumor methylation heterogeneity in the original samples taken from those who went on to relapse than they did in diagnostic tumors from seven individuals who hadn't relapsed in the five or more years after treatment. 

The team verified this pattern through targeted bisulfite sequencing on samples from 59 individuals with DLBCL from another cohort, demonstrating that relatively uniform methylation patterns within a tumor at diagnosis was linked to longer relapse-free survival.