Christina Tatsi1, Nathan Pankratz2, John Lane2, Fabio R Faucz1, Laura C Hernández-Ramírez1, Margaret Keil1, Giampaolo Trivellin1, Prashant Chittiboina3, James L Mills4, Constantine A Stratakis1, Maya B Lodish1. 1. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. 2. Department of Laboratory Medicine and Pathology University of Minnesota Medical School, Minneapolis, Minnesota. 3. Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. 4. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Health, Bethesda, Maryland.
Abstract
CONTEXT: Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined. OBJECTIVE: We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents. SAMPLES AND DESIGN: Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis. RESULTS: Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. CONCLUSIONS: A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD. Published by Oxford University Press on behalf of the Endocrine Society 2019.
CONTEXT: Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined. OBJECTIVE: We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents. SAMPLES AND DESIGN: Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis. RESULTS: Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. CONCLUSIONS: A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD. Published by Oxford University Press on behalf of the Endocrine Society 2019.
Authors: Fanny Chasseloup; Nathan Pankratz; John Lane; Fabio R Faucz; Margaret F Keil; Prashant Chittiboina; Denise M Kay; Tara Hussein Tayeb; Constantine A Stratakis; James L Mills; Laura C Hernández-Ramírez Journal: J Clin Endocrinol Metab Date: 2020-06-01 Impact factor: 5.958
Authors: Idoia Martínez de LaPiscina; Laura C Hernández-Ramírez; Nancy Portillo; Ana L Gómez-Gila; Inés Urrutia; Rosa Martínez-Salazar; Alejandro García-Castaño; Aníbal Aguayo; Itxaso Rica; Sonia Gaztambide; Fabio R Faucz; Margaret F Keil; Maya B Lodish; Martha Quezado; Nathan Pankratz; Prashant Chittiboina; John Lane; Denise M Kay; James L Mills; Luis Castaño; Constantine A Stratakis Journal: Front Endocrinol (Lausanne) Date: 2020-07-03 Impact factor: 5.555