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

Rikke Hjortebjerg; Ulrick Espelund; Torben Riis Rasmussen; Birgitte Folkersen; Torben Steiniche; Jeanette Bæhr Georgsen; Claus Oxvig; Jan Frystyk

doi:10.3389/fendo.2020.00614

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

Rikke Hjortebjerg^*, Ulrick Espelund, Torben Riis Rasmussen, Birgitte Folkersen, Torben Steiniche, Jeanette Bæhr Georgsen, Claus Oxvig, Jan Frystyk

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

4 Citations (Scopus)

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.

Original language	English
Article number	614
Journal	Frontiers in Endocrinology
Volume	11
Number of pages	11
ISSN	1664-2392
DOIs	https://doi.org/10.3389/fendo.2020.00614
Publication status	Published - Sept 2020

Keywords

insulin-like growth factor
insulin-like growth factor binding protein
lung cancer
mortality
pregnancy-associated plasma protein-A
pregnancy-associated plasma protein-A2

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10.3389/fendo.2020.00614Licence: CC BY

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title = "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.",

keywords = "insulin-like growth factor, insulin-like growth factor binding protein, lung cancer, mortality, pregnancy-associated plasma protein-A, pregnancy-associated plasma protein-A2",

author = "Rikke Hjortebjerg and Ulrick Espelund and Rasmussen, {Torben Riis} and Birgitte Folkersen and Torben Steiniche and Georgsen, {Jeanette B{\ae}hr} and Claus Oxvig and Jan Frystyk",

year = "2020",

month = sep,

doi = "10.3389/fendo.2020.00614",

language = "English",

volume = "11",

journal = "Frontiers in Endocrinology",

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Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer. / Hjortebjerg, Rikke; Espelund, Ulrick ; Rasmussen, Torben Riis et al.
In: Frontiers in Endocrinology, Vol. 11, 614, 09.2020.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

AU - Hjortebjerg, Rikke

AU - Espelund, Ulrick

AU - Rasmussen, Torben Riis

AU - Folkersen, Birgitte

AU - Steiniche, Torben

AU - Georgsen, Jeanette Bæhr

AU - Oxvig, Claus

AU - Frystyk, Jan

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - insulin-like growth factor

KW - insulin-like growth factor binding protein

KW - lung cancer

KW - mortality

KW - pregnancy-associated plasma protein-A

KW - pregnancy-associated plasma protein-A2

UR - http://www.scopus.com/inward/record.url?scp=85091050451&partnerID=8YFLogxK

U2 - 10.3389/fendo.2020.00614

DO - 10.3389/fendo.2020.00614

M3 - Journal article

C2 - 32982990

AN - SCOPUS:85091050451

SN - 1664-2392

VL - 11

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

M1 - 614

ER -

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

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Keywords

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