Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer.

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) and its homolog PAPP-A2 are enzymes that modulate the availability and mitogenic activity of insulin-like growth factor-I (IGF-I). PAPP-A has been implicated in numerous cancers but reports on PAPP-A2 in malignancy are non-existent. In a prospective observational study of 689 patients under suspicion of lung cancer, we examined levels of PAPP-A and PAPP-A2 and their relationship with mortality. Serum PAPP-A and PAPP-A2 concentrations were determined in pre-diagnostic blood samples using ELISA, and immunohistochemical staining of PAPP-A and PAPP-A2 was performed in malignant tissue from five operable patients. A total of 144 patients were diagnosed with lung cancer, whereas the diagnosis was rejected in 545 subjects, who served as a control group. PAPP-A2 concentrations were higher in patients with lung cancer [median (IQR): 0.33 (0.21-0.56) ng/mL] than in controls [0.27 (0.17-0.39) ng/mL], p < 0.001, whereas PAPP-A levels did not differ. Presence of PAPP-A and PAPP-A2 were confirmed in tumor specimens, and staining occurred in a heterogeneous pattern. Patients were observed for a median (range) of 7 (6; 8) years, during which 114 patients (79.2%) died. Patient mortality differed according to PAPP-A2 tertile (p < 0.001). PAPP-A2 was associated with mortality with an unadjusted hazard ratio (95% CI) per doubling in protein concentration of 1.30 (1.12; 1.53), p = 0.001. In a multivariable model adjusted for age, sex, and BMI, PAPP-A2 remained predictive of the endpoint with a hazard ratio per doubling in protein concentration of 1.25 (1.05; 1.48), p = 0.013. Collectively, PAPP-A2, but not PAPP-A, is elevated in patients with lung cancer and associated with mortality. This novel role of PAPP-A2 in cancer warrants further functional studies as well as validation in external cohorts.

• Authors: Rikke Hjortebjerg, Ulrick Espelund, Torben Riis Rasmussen, Birgitte Folkersen, Torben Steiniche, Jeanette Bæhr Georgsen, Claus Oxvig, Jan Frystyk
• Journal: Frontiers in endocrinology (Front Endocrinol (Lausanne)) Vol. 11 Pg. 614 ( 2020) ISSN: 1664-2392 [Print] Switzerland
• PMID: 32982990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Hjortebjerg, Espelund, Rasmussen, Folkersen, Steiniche, Georgsen, Oxvig and Frystyk.

Chemical References

• PAPPA2 protein, human
• Pregnancy-Associated Plasma Protein-A

Topics

• Aged
• Aged, 80 and over
• Carcinoma, Non-Small-Cell Lung (blood, mortality)
• Female
• Humans
• Lung Neoplasms (blood, mortality)
• Male
• Middle Aged
• Pregnancy-Associated Plasma Protein-A (metabolism)
• Prognosis
• Small Cell Lung Carcinoma (blood, mortality)