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

Author:

De Sousa Sunita M C123ORCID,McCormack Ann456ORCID,Orsmond Andreas5,Shen Angeline78,Yates Christopher J78,Clifton-Bligh Roderick91011ORCID,Santoreneos Stephen12,King James13,Feng Jinghua1415,Toubia John1415,Torpy David J13,Scott Hamish S31415

Affiliation:

1. Endocrine & Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia

2. South Australian Adult Genetics Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia

3. Adelaide Medical School, University of Adelaide , Adelaide, SA 5000 , Australia

4. Department of Endocrinology, St Vincent's Hospital , Sydney, NSW 2000 , Australia

5. Hormones and Cancer Group, Garvan Institute of Medical Research , Sydney, NSW 2000 , Australia

6. St Vincent's Clinical School, University of New South Wales , Sydney, NSW 2000 , Australia

7. Department of Diabetes and Endocrinology, Royal Melbourne Hospital , Melbourne, VIC 3000 , Australia

8. Department of Medicine, University of Melbourne , Melbourne, VIC 3000 , Australia

9. Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital , Sydney, NSW 2000 , Australia

10. Faculty of Medicine and Health, The University of Sydney , Sydney, NSW 2000 , Australia

11. Department of Endocrinology, Royal North Shore Hospital , Sydney, NSW 2000 , Australia

12. Department of Neurosurgery, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia

13. Department of Surgery, University of Melbourne , Melbourne, VIC 3000 , Australia

14. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and University of South Australia alliance , Adelaide, SA 5000 , Australia

15. ACRF Cancer Genomics Facility, Centre for Cancer Biology, University of South Australia and SA Pathology , Adelaide, SA 5000 , Australia

Abstract

Abstract 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 predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with PAs. As PAs are relatively common and typically lack classic autosomal dominant family histories, risk alleles—such as these variants found in CHEK2—might be a significant contributor to PA risk in the general population.

Funder

Royal Adelaide Hospital

Royal Australasian College of Physicians

Endocrine Society of Australia

Publisher

The Endocrine Society

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1. Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas;The Journal of Clinical Endocrinology & Metabolism;2024-04-23

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