Adrenal (Excluding Mineralocorticoids)

SAT-505 - Expanded Landscape of Gene Fusion Complexity in Pheochromocytomas and Paragangliomas.

Saturday, June 13, 2026

9:30 AM - 4:30 PM CT

Late-Breaking Poster Presenter(s)

Eduardo Cunha Lobato (he/him/his)

Faculdade de Medicina da Universidade de Sao Paulo
Sao Paulo, BRAZIL

Co-Author(s)

CE

Cynthia M Estrada-Zuniga, MD, PhD

University of Texas Health Science Center at San Antonio
San Antonio, TX, United States
AL

Andre F. Lafranchi, MD

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Sao Paulo, Sao Paulo, Brazil
MV

Matheus Virgilio, n/a

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Sao Paulo, Brazil
LR

Lucas B. Rossetti, PhD

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Sao Paulo, Sao Paulo, Brazil
AA

Ana Caroline F Alonso, n/a

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Sao Paulo, Sao Paulo, Brazil
LS

Lucas Santana, PhD

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, BR
Sao Paulo, Brazil
FF

Felipe Freitas-Castro, PhD

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, BR
Sao Paulo, Brazil
MP

Maria Adelaide A Pereira, MD, PhD

Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Sao Paulo, Brazil
DL

Delmar Lourenco, MD, PhD

University of So Paulo
Sao Paulo, Brazil
Ana Hoff, MD, PhD

Chief Endocrine oncology unit
ICESP/University of So Paulo
Sao Paulo, Sao Paulo, Brazil
GF

Gustavo Fagundes, MD, PhD

University of So Paulo, SP Brazil
Sao Paulo, Sao Paulo, Brazil
AL

Ana Claudia Latronico, MD, PhD (she/her/hers)

Sao Paulo Medical School, Sao Paulo University
São Paulo, Sao Paulo, Brazil
AL

Antonio Lerario, MD, PhD

University of Michigan
Ann Arbor, Michigan, United States
PD

Patricia Dahia, MD, PhD

University of TX Health Science Center San Antonio
San Antonio, Texas, United States

Senior Author/Primary Investigator(s)

Madson Almeida, n/a

Professor
University of Sao Paulo
São Paulo, Brazil

Disclosure(s):

Eduardo Cunha Lobato: No financial relationships to disclose

Background:
Pheochromocytomas and paragangliomas (PPGLs) are rare
neuroendocrine neoplasms from the adrenal medulla or sympathetic/parasympathetic
ganglia, respectively. Although some genotypes are associated with higher metastatic
risk (SDHB gene and MAML3 fusions), there are few predictors of metastatic
progression. This study characterized a Brazilian cohort of PPGLs through
transcriptomic analysis, with particular focus on metastatic tumors and fusion events.

Methods:
Tumor RNAs from frozen samples of 44 PPGLs from 43 patients (33
pheochromocytoma and 10 paraganglioma; 15 metastatic) were subjected to RNA
sequencing (Illumina). Genotypes included: SDHB (n=6), NF1 (n=6), RET (n=5);
HRAS, EPAS1, VHL and H3F3A (n=3 each); and SDHD, MAX, and FGFR1 (n=1 each).
Twelve PPGLs had unknown genetic status. Our dataset was integrated with two
independent PPGL datasets for comparative cluster analysis (n=242). Fusion genes were
confirmed by RT-PCR.

Results:
RNA sequencing identified 5 gene fusions (11.6%), including a novel
DLG5::RET in-frame fusion gene in one patient with unknown genotype; this sample
clustered within the kinase signaling group, and with a RET::GRB2 fusion from
integrated cohorts, supporting its pathogenic role. MAML3 fusions were identified in
four patients (TCF4::MAML3 (n=2) and UBTF::MAML3(n=2)). Unsupervised
clustering allowed a good discrimination of samples based on genotype, including
metastatic PPGLs with previously known drivers (5 SDHB, 3 NF1, 2 MAML3, SDHD,
HRAS, H3F3A and RET), that clustered by genotype rather than by metastatic behavior.
TCF4::MAML3 tumors were part of a distinct cluster, separate from UBTF::MAML3
tumors, and co-clustered with MAX- and H3F3A-related tumors. This pattern was
reproducible when integrating data from external cohorts: our TCF4::MAML3 samples
co-clustered with other available TCF4 tumors (n=2), whereas UBTF::MAML3 samples
co-clustered with other UBTF::MAML3 PPGLs. Both PPGLs with TCF4::MAML3
fusions were metastatic, whereas those with UBTF::MAML3 have remained non-
metastatic to date (median follow-up 25.5 months). All MAML3 fusion PPGLs were
noradrenergic (n=4).

Conclusion:

We identified 11.6% of fusion genes in this cohort, including two cases of
the rare TCF4::MAML3 fusion and a novel DLG5::RET fusion. TCF4::MAML3 tumors
displayed a distinct transcriptomic profile from UBTF::MAML3, and were associated
with metastatic disease. These findings support the existence of biologically distinct
MAML3-rearranged subgroups that may be driven by the upstream fusion partner and
suggest that TCF4::MAML3 defines a higher-risk subtype within PPGLs.

Support: Sao Paulo Research Foundation (FAPESP; 2019/15873-6, 25/24129-0 and 2025/00196-0)
and National Council for Scientific and Technological Development (CNPq;
304091/2021-9). NIH-NCI CA264248.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*