Unmasking Cancer Risk in Heritable PAH - The Hidden Role of BMPR2 in Epithelial Tumorigenesis

Sep 23, 2026

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BMPR2 mutations drive heritable pulmonary arterial hypertension (PAH) and may contribute to epithelial carcinogenesis. Three women with BMPR2-related heritable PAH developed early-onset epithelial cancers while receiving advanced PAH therapy: two breast cancers at ages 34 and 54, and one colorectal cancer at age 47. Genetic testing of first-degree relatives was negative for the family BMPR2 variant, and additional oncogenetic workup excluded BRCA and Lynch syndrome.

LanguageEnglish

CategoryHealthcare

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Pages5

Reading Time13 min

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Abstract

Background

Case Summary

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Case Reports

JA CC: CASE REPORTS VOL . 30, NO . 32, 2025 © 2025 THE AUTHORS . PUBLISHED BY ELSE VIE R ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION . THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY LICENSE ( [http://creative commons . org/licenses/by/4 . 0/](http://creative commons . org/licenses/by/4 . 0/) ) . CARDIO-ONCOLOGY CLINICAL CASE SERIES Unmasking Cancer Risk in Heritable PAH The Hidden Role of BMPR2 in Epithelial Tumorigenesis Belén Biscotti Rodil, MD,a Alejandro Cruz-Utrilla, MD, PHD,a,b Irene Martín de Miguel, MD,a,b Jorge Barriuso, MD, PHD,c Fernando Arribas Ynsaurriaga, MD, PHD,b,d Pilar Escribano Subías, MD, PHDa,b ABSTRACT BACKGROUND BMPR2 mutations cause heritable pulmonary arterial hypertension (PAH) and may also influence epithelial carcinogenesis. CASE SUMMARY We report 3 women with BMPR2-related PAH who developed early onset epithelial cancers: 2 breast cancers (34 and 54 years of age) and 1 colorectal cancer (47 years of age) . All were on advanced PAH therapy at diagnosis. Genetic screening of relatives was negative, and additional oncogenetic testing excluded BRCA and Lynch syndrome. Management included chemotherapy, surgery in 2 cases, and palliative care in 1 case. DISCUSSION BMPR2, essential for vascular homeostasis, is also implicated in tumor suppression and modulation of the tumor microenvironment. In our cohort of 32 patients, epithelial cancer prevalence was 9.4%, with diagnosis at significantly younger ages than the general population. These findings suggest a potential oncogenic role for BMPR2 mutations and the need for further research. TAKE-HOME MESSAGE BMPR2 mutations may predispose to early onset epithelial cancers, warranting investigation into cancer risk and screening strategies in this population. (JACC Case Rep. 2025;30:105344) © 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). W e present 3 cases of epithelial neoplasms in 3 women with heritable pulmonary arterial hypertension (PAH) associated with mutations in the BMPR2 gene under advanced therapy, all diagnosed at an early age. The neoplasms correspond to 2 cases of breast cancer at 34 and 54 years of age, and 1 case of colorectal cancer at 47 years of age. The first case involves a 34-year-old woman diagnosed with heritable PAH due to a pathogenic BMPR2 mutation in 2017 after an episode of hemoptysis. Dual oral therapy with tadalafil and ambrisentan was initiated at diagnosis, and she remained at low risk on this regimen until 2022, when selexipag was added. In April 2024, she experienced a new episode of hemoptysis requiring embolization. Given the echocardiographic and hemodynamic deterioration, subcutaneous treprostinil was initiated and titrated to 32 ng/kg/min. In October of the same year, she was diagnosed with triple-negative infiltrating ductal From the aPulmonary Hypertension Multidisciplinary Unit, Cardiology Department, Hospital Universitario 12 de Octubre, and CIBERCV, Madrid, Spain; bInstituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain; cOncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; and the dCardiology Department, Hospital Universitario 12 de Octubre, and CIBERCV, Madrid, Spain. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. Manuscript received July 3, 2025; revised manuscript received August 4, 2025, accepted August 5, 2025. ISSN 2666-0849 [https://doi.org/10.1016/j.jaccas.2025.105344](https://doi.org/10.1016/j.jaccas.2025.105344) 2 Biscotti Rodil et al J A C C : C A S E R E P O R T S , V O L . 3 0 , N

FAQs

What relationship between BMPR2 mutations and cancer risk is suggested in these cases?

BMPR2 mutations associated with heritable PAH may predispose patients to early-onset epithelial cancers, based on the cancers observed in three treated women and the cohort findings discussed.

What types of epithelial cancers occurred in the reported patients?

Two patients developed breast cancer, and one patient developed colorectal cancer. Ages at diagnosis were 34, 54, and 47 years, respectively.

How were familial and hereditary cancer syndromes evaluated?

First-degree relatives underwent genetic screening and did not carry the identified BMPR2 mutation. Additional oncogenetic testing excluded BRCA and Lynch syndrome.

Sep 23, 2026

Uploaded by hdkawk