Gene

Prolactinoma

Digital polymerase chain reaction

Biology

Endocrinology

Somatic cell

Mutation

Cancer research

Immunology

Genetics

Germline mutation

RNA splicing

Prolactin

Mutant

Hormone

Polymerase chain reaction

Pathogenesis

Nature Communications

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 ( SF3B1 R625H ) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels ( p = 0.02) and shorter progression-free survival (PFS) ( p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1 R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

Somatic SF3B1 hotspot mutation in prolactinomas