Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar
{"title":"Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors","authors":"Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar","doi":"10.1007/s00401-024-02736-8","DOIUrl":null,"url":null,"abstract":"<div><p>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 (<i>n</i> = 66) who consented to sequencing prior to surgery and a retrospective group (<i>n</i> = 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 (<i>p</i> = 1.3 × 10<sup>−10</sup> and <i>p</i> = 8.5 × 10<sup>−9</sup>, 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, <i>p</i> = 1.7 × 10<sup>−4</sup>). Across the cohort, a higher fraction of LOH was identified in tumors with <i>TP53</i> mutations (<i>p</i> = 3.3 × 10<sup>−8</sup>). 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, <i>TP53</i>, 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.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3000,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02736-8.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-024-02736-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.