MACROD2 and CDKN2A in multiple myeloma: Insights to germline susceptibility and cytogenetic risk from long-read Nanopore sequencing.
Year: 2026
Type: conference-abstract
Abstract: e19566 Background: The MACROD2 gene is a chromosomal fragile site that undergoes frequent intragenic deletions in human carcinomas. Structural features of the deletions have argued against a tumor suppressor role, but functional studies have implicated the MACROD2 mono-ADP-ribosylhydrolase, acting via PARP1, in maintaining chromosomal stability and preventing aneuploidies. The role of this gene in multiple myeloma (MM), a cancer with recurrent aneuploidies that arise at the early MGUS stage, has not been well studied. In contrast, CDKN2A is a classical tumor suppressor whose deletion is linked to aggressive disease and poor prognosis in MM, and it is also a germline susceptibility locus for this disease. Here we present new molecular findings bearing on the roles of these two genes in MM. Methods: To correlate genetic and epigenetic features, we analyzed a series of MM cases, often paired with peripheral blood, using Illumina EPIC Beadchips and long-read Oxford Nanopore sequencing. In total, CD138-positive MM cells from 57 patients were included, of which 49 were profiled using EPIC arrays and 22 underwent whole-genome Nanopore sequencing, with 14 cases analyzed on both platforms. This approach enabled high-resolution characterization of CpG methylation, DNA structural lesions, and chromosomal copy number aberrations (CNAs). Results: Data from both Nanopore and EPIC revealed a 220Kb germline hemizygous deletion spanning MACROD2-AS1 , a lncRNA embedded in the 2Mb MACROD2 gene, in a familial MM case. The patient, whose father had MM and mother had lymphoma, was diagnosed with MGUS at age 50 following unexpected osteopenia, with progression to MM by age 64. In our full series of MM cases, CpG hypermethylation of the MACROD2 promoter was associated with hyperdiploidy and Chr1q gain (Fisher exact test, p = 0.04 and p = 0.02 respectively). In contrast, promoter methylation of CDKN2A was seen in a mostly non-overlapping set of cases and was strongly associated with cytogenetically high-risk disease (Fisher’s exact test, p = 8 × 10⁻⁴), but not with hyperdiploidy. Importantly for mechanisms involving hemizygosity and gene dosage, the Nanopore data revealed allele specific DNA methylation in both genes in MM cells. Conclusions: The hemizygous germline MACROD2-AS1 deletion in the familial MM case and the association of MACROD2 promoter methylation with Chr1q gains and hyperdiploid disease in our case series suggest a role for genetic and epigenetic lesions in this gene at early stages of MM tumor development. In contrast, CDKN2A hypermethylation appears promising as an epigenetic marker for aggressive high-risk MM cases.
Source: Journal of Clinical Oncology
Authors: Panteha Behboodi, James Di Palma Grisi, Andy Madrid, Martha Salas, Angelica Castano, Reilly Kobbe, Carolina Alberca, Mariam Tariq, Mauricio Rigo, Rohan Sarkar, Lara Sucheston-Campbell, Kar Chow, Jens Hillengass, Michael Slade, Samir S. Parekh, Alessandro Lagana, Noa Biran, David Samuel DiCapua Siegel, Rena Feinman, Benjamin Tycko
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7162689188
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