Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

PAM and CHEK2 are emerging pituitary tumour predisposition genes: novel findings from an Australian multicentre cohort (#30)

Sunita De Sousa 1 2 3 , Ann McCormack 4 5 6 , Andreas Orsmond 5 , Angeline Shen 7 8 , Christopher Yates 7 8 , Roderick Clifton-Bligh 9 10 11 , Stephen Santoreneos 12 , James King 13 , Jinghua Feng 14 15 , John Toubia 14 15 , David Torpy 1 3 , Hamish Scott 3 14 15
  1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  2. SA Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  3. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  4. Department of Endocrinology, St Vincent's Hospital, Sydney, NSW, Australia
  5. Garvan Institute of Medical Research/St Vincent's Hospital, Darlinghurst, NSW, Australia
  6. St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
  7. Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC, Australia
  8. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
  9. Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia
  10. School of Medicine, The University of Sydney, Sydney, NSW, Australia
  11. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
  12. Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, SA, Australia
  13. Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
  14. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  15. ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia

Aims: We aimed to investigate candidate pituitary tumorigenesis genes. PAM, encoding an enzyme involved in peptide hormone biosynthesis, has a long-established role in type 2 diabetes but it was only implicated in pituitary tumorigenesis in 2023, with an NIH-based group finding enrichment of variants in the pituitary adenoma setting (1). CHEK2 is a cell cycle checkpoint regulator gene implicated in breast cancer and other neoplasia (2); it has not previously been studied in pituitary adenomas. 

Methods: The overall study population comprised 165 Australian adults with pituitary adenomas. This consisted of a primary cohort of 29 individuals who underwent whole exome sequencing of germline and tumour DNA, and a secondary cohort of 136 individuals who had a targeted next generation sequencing panel (including CHEK2 but not PAM) of germline and tumour DNA (n=52) or germline DNA alone (n=84). We performed bioinformatic analysis to identify rare, coding, non-synonymous variants in PAM (primary cohort only) and CHEK2 (both cohorts). As CHEK2 is a well-characterised disease-causing gene, variants could be classified as ‘pathogenic’/‘likely pathogenic’ using international criteria.

Results: We demonstrated five predicted deleterious PAM variants in 7/29 (24%) individuals in the primary cohort (six germline, one somatic), and four pathogenic/likely pathogenic CHEK2 variants in 5/165 (3%) individuals from the combined cohorts (all germline). Pathogenic CHEK2 variants were over-represented in our patients compared to Australian controls (1.8% vs. 0.5%, P=0.049).

Conclusion: This is the first study to link CHEK2, and the second to link PAM, to pituitary adenomas. We also identified new associations between PAM and cyclical Cushing’s disease/thyrotrophinomas. Our findings raise a novel hypothesis that relatively common, lower penetrant variants – such as the PAM/CHEK2 variants observed here – might act as ‘risk alleles’ in pituitary tumorigenesis, potentially explaining both the high population prevalence of pituitary adenomas and typically incomplete inheritance patterns (3,4).

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  1. Trivellin G, Daly AF, Hernández-Ramírez LC, et al. Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion. Front Endocrinol (Lausanne). 2023;14:1166076.
  2. Hanson H, Astiazaran-Symonds E, Amendola LM, et al. Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(10):100870.
  3. De Sousa SMC, McCormack A, Orsmond A, et al. Increased prevalence of germline pathogenic CHEK2 variants in individuals with pituitary adenomas. J Clin Endocrinol Metab. 2024.
  4. De Sousa SMC, Shen A, Yates CJ, et al. PAM variants in patients with thyrotrophinomas, cyclical Cushing's disease and prolactinomas. Front Endocrinol (Lausanne). 2023;14:1305606.