Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling
by
, , , , , , , ,
Oscar Lopez-Nunez
1,†
,
Rita Alaggio
2,*,†,
Ivy John
3,
Andrea Ciolfi
4,
Lucia Pedace
5,
Angela Mastronuzzi
5
,
Francesca Gianno
6,
Felice Giangaspero
6,7,
Sabrina Rossi
2,
Vittoria Donofrio
8,
Giuseppe Cinalli
8,
Lea F. Surrey
9,
Marco Tartaglia
4,
Franco Locatelli
5,10 and
Evelina Miele
5,*
1
Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
2
Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
3
Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
4
Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
5
Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
6
Radiologic, Oncologic and Anatomo-Pathological Sciences Department, Sapienza University, 00161 Rome, Italy
7
IRCCS Neuromed, Pozzilli, 86077 Isernia, Italy
8
Pathology Unit, Azienda Ospedaliera Santobono-Pausilipon, 80122 Naples, Italy
9
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
10
Department of Pediatrics, Sapienza University of Rome, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
†
Both authors share equal contribution as first authors.
Cancers 2021, 13(4), 706; https://doi.org/10.3390/cancers13040706
Submission received: 4 January 2021
/
Revised: 3 February 2021
/
Accepted: 5 February 2021
/
Published: 9 February 2021
(This article belongs to the Special Issue Pediatric Brain Tumors)
Simple Summary
Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor of uncertain origin, morphologically overlapping other rare neoplasms such as pineal anlage tumor (PAT) and a subset of medulloblastomas (i.e., melanotic medulloblastoma). Despite the similarities with MNTI, their possible histogenetic relationship has been traditionally disregarded based on their aggressive behavior and dismal prognosis. The aim of this study was to further characterize the molecular features of MNTI and PAT based on DNA-methylation and copy number variation profiling analysis. We found that MNTI shares a methylation profile with group 3 high-risk medulloblastoma, and potentially with PAT, suggesting a common histogenesis. Most MNTIs in our series lacked copy number variation alterations, whereas their presence in the one PAT deserves further study in larger cohorts to better determine their impact in prognosis and biologic behavior.
Abstract
MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
