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A Sonic Hedgehog Pathway Score to Predict the Outcome of Resected Non-Small Cell Lung Cancer Patients

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Abstract

Background

Mutations and deregulations in components of the Hedgehog (Hh) pathway have been associated with cancer onset and tumor growth in different malignancies, but their role in non-small cell lung cancer (NSCLC) remains unclear. This study aims to investigate the expression pattern of the main components of the Hh pathway in tumor and adjacent normal tissue biopsies of resected NSCLC patients.

Methods

The relative expression of GLI1, PTCH1, SHH, and SMO was analyzed by quantitative polymerase chain reaction (PCR) in a cohort of 245 NSCLC patients. Results were validated in an independent cohort of NSCLC patients from The Cancer Genome Atlas (TCGA).

Results

We found that SMO and GLI1 were overexpressed in the tumor compared with normal-paired tissue, whereas PTCH1 and SHH were underexpressed. In addition, patients with higher expression levels of PTCH1 presented better outcomes. A gene expression score, called the Hedgehog Score, was calculated using a multivariable model including analyzed components of the Hh signaling pathway. NSCLC patients with a high Hedgehog Score had significantly shorter relapse-free survival (RFS) and overall survival (OS) than patients with a low score, especially at stage I of the disease. Similarly, patients in the adenocarcinoma (ADC) subcohort had shorter RFS and OS. Multivariate Cox analysis exhibited that the Hedgehog Score is an independent prognostic biomarker for OS in both the entire training cohort and the ADC subcohort. The Hedgehog Score was validated in an independent cohort of NSCLC patients from TCGA, which confirmed its prognostic value.

Conclusions

Our results provide relevant prognostic data for NSCLC patients and support further studies on the Hh pathway.

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Acknowledgments

This work was supported by grant no. CB16/12/00350 from the Centro de Investigación Biomédica en Red de Cáncer (CIBEROnc) and Grant No. PI18/00266 from the Instituto de Salud Carlos III (ISCIII).

Author information

Author notes

  1. Carlos Camps and Eloísa Jantus-Lewintre equally supervised this work.

Authors and Affiliations

  1. Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain

    Alejandro Herreros-Pomares PhD & Eloísa Jantus-Lewintre PhD

  2. Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain

    Alejandro Herreros-Pomares PhD, Sandra Gallach PhD, Ricardo Guijarro MD, PhD, Silvia Calabuig-Fariñas PhD, Carlos Camps MD, PhD & Eloísa Jantus-Lewintre PhD

  3. Persona Biomed Spain S.L., Valencia, Spain

    Paula Doria MSc

  4. Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, Valencia, Spain

    Sandra Gallach PhD, Silvia Calabuig-Fariñas PhD, Carlos Camps MD, PhD & Eloísa Jantus-Lewintre PhD

  5. TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación Investigación del Hospital General Universitario de Valencia, Valencia, Spain

    Sandra Gallach PhD, Ricardo Guijarro MD, PhD, Silvia Calabuig-Fariñas PhD, Carlos Camps MD, PhD & Eloísa Jantus-Lewintre PhD

  6. Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain

    Marina Meri-Abad MD & Carlos Camps MD, PhD

  7. Department of Surgery, Universitat de València, Valencia, Spain

    Ricardo Guijarro MD, PhD

  8. Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain

    Ricardo Guijarro MD, PhD

  9. Department of Pathology, Universitat de València, Valencia, Spain

    Silvia Calabuig-Fariñas PhD

  10. Department of Medicine, Universitat de València, Valencia, Spain

    Carlos Camps MD, PhD

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  1. Alejandro Herreros-Pomares PhD
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Correspondence to Alejandro Herreros-Pomares PhD or Eloísa Jantus-Lewintre PhD.

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Alejandro Herreros-Pomares, Paula Doria, Sandra Gallach, Marina Meri-Abad, Ricardo Guijarro, Silvia Calabuig-Fariñas, Carlos Camps, and Eloísa Jantus-Lewintre declare no conflicts of interest.

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Herreros-Pomares, A., Doria, P., Gallach, S. et al. A Sonic Hedgehog Pathway Score to Predict the Outcome of Resected Non-Small Cell Lung Cancer Patients. Ann Surg Oncol 30, 1225–1235 (2023). https://doi.org/10.1245/s10434-022-12565-2

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