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- Title
Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.
- Authors
Lin, Andrew L.; Rudneva, Vasilisa A.; Richards, Allison L.; Zhang, Yanming; Woo, Hyung Jun; Cohen, Marc; Tisnado, Jamie; Majd, Nazanin; Wardlaw, Sharon L.; Page-Wilson, Gabrielle; Sengupta, Soma; Chow, Frances; Goichot, Bernard; Ozer, Byram H.; Dietrich, Jorg; Nachtigall, Lisa; Desai, Arati; Alano, Tina; Ogilive, Shahiba; Solit, David B.
- Abstract
Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10−10 and p = 8.5 × 10−9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10−4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10−8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.
- Subjects
PITUITARY tumors; NEUROENDOCRINE tumors; HETEROZYGOSITY; BENIGN tumors; MACHINE learning; DEEP brain stimulation
- Publication
Acta Neuropathologica, 2024, Vol 147, Issue 1, p1
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-024-02736-8