Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas

作者：Sunita M C De Sousa, Ann I. McCormack, Andreas Orsmond, Angeline Shen, Christopher James Yates, Roderick John Clifton-Bligh, Stephen Santoreneos, James A. J. King, Jinghua Feng, John Toubia, David James Torpy, Hamish S. Scott · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2024 · DOI：10.1210/clinem/dgae268 · 被引用次数：8 · 研究领域：BRCA gene mutations in cancer、Pituitary Gland Disorders and Treatments、Genomics and Rare Diseases

CONTEXT: CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. OBJECTIVE: To assess the rate and pathogenicity of CHEK2 variants amongst individuals with pituitary adenomas (PAs). METHODS: We assessed 165 individuals with PAs for CHEK2 variants. The study population comprised a primary cohort of 29 individuals who underwent germline and tumor whole-exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumor DNA (n = 52) or germline DNA alone (n = 84). RESULTS: We identified rare, coding, nonsynonymous germline CHEK2 variants amongst 3 of 29 (10.3%) patients in our primary cohort, and in 5 of 165 (3.0%) patients overall, with affected patients having a range of PA types (prolactinoma, thyrotropinoma, somatotropinoma, and nonfunctioning PA). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444 + 1G > A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs 0.5%; P = .049). CONCLUSION: This is the first study to suggest a role for the breast cancer predispositi...