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Loss and Reduction of Fus1 Protein Expression is a Frequent Phenomenon in the Pathogenesis of Lung Cancer

Authors' Affiliations: Departments of ¹ Pathology, ² Thoracic/Head and Neck Medical Oncology, ³ Biostatistics and Applied Mathematics, and ⁴ Thoracic Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ⁵ Hamon Center for Therapeutic Oncology Research, and Departments of ⁶ Internal Medicine and ⁷ Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Ignacio I. Wistuba, Department of Pathology, Unit 85, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-563-9184; Fax: 713-792-0309; E-mail: iiwistuba{at}mdanderson.org.

Purpose: FUS1, a novel tumor-suppressor gene located in the chromosome 3p21.3 region, may play an important role in lung cancer development. Currently, FUS1-expressing nanoparticles have been developed for treating patients with lung cancer. However, the expression of Fus1 protein has not been examined in a large series of lung cancers and their sequential preneoplastic lesions.

Experimental Design: Using tissue microarrays, we examined Fus1 immunohistochemical expression in 281 non–small cell lung carcinoma (NSCLC) and 22 small cell lung carcinoma tissue specimens and correlated the findings with patients' clinicopathologic features. To investigate the expression of Fus1 in the early sequential pathogenesis of NSCLC, we studied Fus1 expression in 211 histologically normal and mildly abnormal bronchial epithelia, and 118 bronchial and alveolar preneoplastic lesions obtained from patients with lung cancer.

Results: Loss and reduction of expression was detected in 82% of NSCLCs and 100% of small cell lung carcinomas. In NSCLCs, loss of Fus1 immunohistochemical expression was associated with significantly worse overall survival. Bronchial squamous metaplastic and dysplastic lesions expressed significantly lower levels of Fus1 compared with normal (P = 0.014 and 0.047, respectively) and hyperplastic (P = 0.013 and 0.028, respectively) epithelia.

Conclusions: Our findings show a high frequency of Fus1 protein loss and reduction of expression in lung cancer, and suggests that this reduction may play an important role in the early pathogenesis of lung squamous cell carcinoma. These findings support the concept that FUS1 gene and Fus1 protein abnormalities could be used to develop new strategies for molecular cancer therapy for a significant subset of lung tumors.

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