Researchers at UCSF have recently discovered a polymorphism in the gene TP53 that influences the growth of non-functional pituitary adenomas (NFPAs). TP53 is known to be dysregulated in many human cancers, including brain cancers. But there have been few studies to date on how it may fit in to the development of pituitary tumors.
“Research into the genetic etiology of brain tumors has primarily been focused on gliomas because there are so few effective therapeutic targets for those tumors,” said Manish Aghi, MD, PhD, who led the study published in Molecular and Cellular Endocrinology. “The genetic signatures of pituitary tumors, which are widely considered benign, remain largely unidentified.”
NFPAs – those that do not produce hormones – can often be effectively cured with surgery, but invasive variants that spread into critical neuroanatomical structures can cause permanent deficits and profoundly impact quality of life. The ability to identify patients at greater risk for malignancy could help physicians intervene earlier with aggressive treatments and better counsel patients on expected outcomes.
Based on previous evidence that loss of p53 contributed to pituitary tumor growth, Garima Yagnik, PhD, a geneticist and postdoctoral researcher in the Aghi laboratory, began sequencing the entire TP53 gene in NFPAs, looking for a mutation or polymorphism that could be matched to degree of invasiveness or tumor size.
Almost 80% of the 42 NFPAs sequenced harbored the single nucleotide polymorphism rs1042522:C>G. The G variant found in these NFPAs produces arginine, while the C variant, which was much more common in the general population, produces proline. Yagnik and Aghi found a similarly high rate of rs1042522:C>G in a smaller sample of prolactinomas, further suggesting that alterations in the TP53 gene does promote the development of pituitary tumors.
While the polymorphism did not correlate with tumor size or invasiveness, patients with the G/G allele had symptomatic tumors a decade earlier than those with C/C or C/G. The G/G allele was also associated with a much higher rate of adenoma cell proliferation and reduced p21 transcription, which is important for stopping cell growth.
“We know very little about the biology of these tumors and how they form,” said Yagnik. “But this gives us another piece of the puzzle. The more we know about the genetic characteristics of each tumor type, the better we will be able to predict their natural history and counsel patients on treatment options.”