Abstract Details

Title Aberrant Somatic Hypermutation Plays Minor Role in the Evolution of Molecular Alterations at Recurrence in PCNSL

Topic Neuro-oncology

Presentation(s) P8 - Poster Session 8 (8:00 AM-9:00 AM)

Poster/Presentation
Number 6-010

Objective This study investigates if aSHM is a driving event in recurrent/refractory CNS lymphoma by comparing genomic alterations in archival tumor from diagnosis with circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CFS) at recurrence.

Background Primary CNS lymphoma is a lymphoma exclusively in the CNS. Over half of patients with CNS lymphoma have disease recurrence following initial response to therapy. Aberrant somatic hypermutation (aSHM) is a mechanism of genomic instability in systemic DLBCL and PCNSL.

Design/Methods 10 paired PCNSL patient samples (archival tumor biopsy and CSF at recurrence) were collected. Samples analyzed using MSK-HemePACT panel. For concordance analysis of pairs, mutations designated as “present” when independently detected. Secondary mutation analysis performed to detect the compilation of SNVs detectable within samples (CSF and tumor). Mutations considered “present” if the Variant Allele Depth was ≥ 2 and Variant Allele Frequency ≥ 1%. We used previously published criteria (Khodabakhshi et al., Oncotarget 2012) to determine whether a mutation was the result of aSHM.

Results Interval between tumor biopsy and CSF collection ranged from 1-146 months. Median number of mutations in tumor tissue was 23 vs. 16 in the CSF. 46.8% of SNVs shared between tumor tissue and CSF ctDNA. Most private mutations were found in tumor tissue>CSF samples (35.5% vs. 13.5%). Private mutations in the tumor sample were more frequently a result of aSHM (7.3%) than those in the CSF (0.6%). Shared mutations did not show the hallmarks of aSHM. Driver mutations in the B-cell receptor pathway were generally shared.

Conclusions aSHM was observed in the archival tumor samples that were not shared with the CSF samples. Moreover, aSHM seemed to be a minor contributor to mutations identified in CSF samples. Possibly, aSHM does not play a role in PCNSL after initial diagnosis and therapy, accounting for sparsity of mutations caused by aSHM in recurrent/refractory CSF samples.

Authors/Disclosures
Jennifer H. Newman, MD (Jefferson Neurology) PRESENTER	Dr. Newman has nothing to disclose.
Lauren Schaff, MD, FAAN (Memorial Sloan Kettering Cancer Center)	Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BTG, plc. The institution of Dr. Schaff has received research support from BTG, plc. Dr. Schaff has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Ono.
Lisa M. DeAngelis, MD, FAAN	Dr. DeAngelis has received publishing royalties from a publication relating to health care.
Ingo K. Mellinghoff, MD, FACP (Memorial Sloan Kettering Cancer Center)	Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Agios. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Black Diamond Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Voyager Therapeutics . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kazia Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Agios. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Black Diamond Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Debiopharm Group. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Puma Biotechnology. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Voyager Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for DC Europa Ltd. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kazia Therapeutics. Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis . Dr. Mellinghoff has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cardinal Health. Dr. Mellinghoff has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Servier . Dr. Mellinghoff has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for ASCO/JCO. The institution of Dr. Mellinghoff has received research support from Amgen. The institution of Dr. Mellinghoff has received research support from General Electric. The institution of Dr. Mellinghoff has received research support from Lilly. The institution of Dr. Mellinghoff has received research support from Kazia Therapeutics. An immediate family member of Dr. Mellinghoff has received research support from Vigeo Therapeutics. The institution of an immediate family member of Dr. Mellinghoff has received research support from Samus Therapeutics. The institution of Dr. Mellinghoff has received research support from Erasca .
Christian Grommes, MD (Memorial Sloan-Kettering Cancer Center)	Dr. Grommes has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono. Dr. Grommes has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BTG. Dr. Grommes has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Grommes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Curis. Dr. Grommes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Ono.

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