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Benign Hypertension-Causing Tumors Linked to Somatic Codriver Mutations

NEW YORK – An international team has identified new somatic mutations behind a subset of aldosterone-producing adenomas — benign tumors that form in the adrenal gland and lead to high blood pressure.

The tumor causes the enhanced production of the aldosterone hormone, which in turn leads to salt retention in the kidneys and elevated blood pressure.

"Primary aldosteronism is a major cause of hypertension," co-senior and co-corresponding author Morris Brown, an endocrine hypertension researcher at Queen Mary University of London, and his colleagues explained in a study published in Nature Genetics on Thursday. "This is potentially curable when due to an APA in one adrenal [gland]. Conversely, when primary aldosteronism is overlooked, it leads to resistant hypertension and high cardiovascular risk."

For their study, the researchers used sequencing strategies to focus in on codriver somatic mutations that appear to prompt APA development during puberty, pregnancy, or menopause when levels of certain hormones spike. In particular, their follow-up gene expression, functional, and phenotypic analyses suggested that APAs can turn up in individuals with mutations in the CTNNB1 and the GNA11 or GNAQ genes when such hormones ping a luteinizing hormone (LH)/human chorionic gonadotropin (HCG) receptor, or LHCGR, which is significantly upregulated in APA cases with these dual driver mutations.

"The most obvious clinical implication is to think of the diagnosis of primary aldosteronism in a patient with sudden onset of hypertension at times when there has been a recent increase in hormones [that stimulate LHCGR]," Brown explained in an email.

For their study, the investigators started with exome sequencing on matched tumor and germline samples from 41 individuals with APA, identifying hotspot somatic mutations in ion channel or transporter genes such as CACNA1D or KCNJ5 in dozens of the samples.

But another set of tumors caught their attention as well: three tumors containing mutations in the known APA-related gene CTNNB1 that were also marked by recurrent gain-of-function mutations affecting the G-protein-coding gene GNA11.

With follow-up analyses on exome, targeted DNA, or RNA sequence data for another 27 CTNNB1-mutated APA cases from cohorts in the UK, France, or Sweden, the team flagged 16 more somatic mutations in either GNA11 or in a G-protein subunit-coding gene called GNAQ.

The gain-of-function mutations in GNA11/GNAQ appeared to act as codrivers in a subset of APA cases marked by CTNNB1 mutations that bump up aldosterone production when LH or HCG hormone levels are high, the researchers reported. Indeed, Brown noted, many of the APA cases in which they found the codriver mutations involved pregnant women who began showing symptoms during their first trimester — a time when HCG rises steeply. Another patient was going through early menopause, and three more cases stretched back to puberty.

"Our findings suggest that onset of hypertension in the first trimester — the period of peak HCG secretion — should prompt consideration of PA," the authors suggested, emphasizing that the APA-related form of hypertension is distinct from pregnancy-related hypertension that usually occurs later in pregnancy.

"[O]ur patients are diagnosed relatively quickly because of the explosive onset of PA, when the 'dormant' LHCGR sees its stimulatory hormone," Brown explained, noting that all 16 APA cases involving the newly detected somatic mutation combination were successfully treated with surgery to remove the affected adrenal gland.

Such treatments appear to be curative in just a subset of all APA cases, perhaps owing to the longer aldosterone exposure and hypertension in individuals with forms of the condition that do not occur in response to specific hormone spikes, he noted. However, the investigators are also considering the possibility that the CTNNB1- and GNA11/GNAQ-muted forms of APA may be more apt to produce adrenal gland effects that are unilateral rather than contralateral.

"Clearly there are many missing pieces in this jigsaw," Brown said. "But I suspect our double-mutant patients lie at one extreme of the 'curability' spectrum, and hence understanding the mechanism of their [primary aldosteronism] will hopefully help understanding of what determines likelihood of complete cure."