The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours.

Purpose: Heritable genetic contributions to familial and sporadic pituitary tumorigenesis are poorly understood. There is emerging evidence that germline variants in classical cancer susceptibility genes may increase the risk of pituitary tumour development. We aimed to identify and assess the rate of pathogenic germline variants in breast and colorectal cancer susceptibility genes that may promote pituitary tumorigenesis.

Methods: Using a next-generation sequencing panel, we analysed 26 cancer susceptibility genes in 136 patients with suspected familial or sporadic pituitary tumours. Rates of pathogenic germline variation were compared against the gnomAD database.

Results: We identified nine pathogenic or likely pathogenic germline variants in eight patients, within ATM, BRCA2, CHEK2, MUTYH, MLH1 and APC. We also detected three pathogenic somatic variants in TP53 and MSH6 in two patients. Compared to the general population, more pathogenic germline variants in cancer predisposition genes were found in patients with pituitary tumours (relative rate 1.44, p = 0.46), particularly in mismatch repair genes, albeit not statistically significant. We additionally identified a trend of a larger burden of pathogenic cancer susceptibility gene variants in individuals with classical pituitary tumour predisposition pathogenic variants, compared to those without (29% vs. 4.7%, p = 0.057).

Conclusion: Our study provides a basis for ongoing research into the potential role of cancer susceptibility genes in driving pituitary tumorigenesis.