Complete Loss of PTEN Protein Expression Correlates with Shorter Time to Brain Metastasis and Survival in Stage IIIB/C Melanoma Patients with BRAFV600 Mutations
Open Access
- 30 October 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 20 (21), 5527-5536
- https://doi.org/10.1158/1078-0432.ccr-14-1027
Abstract
Purpose: Loss of function of PTEN is a frequent event in melanoma, particularly in tumors with BRAFV600 mutations. The prevalence, pathologic features, and clinical outcomes associated with PTEN loss in patients with stage IIIB/C melanoma were interrogated to improve our understanding of the clinical significance of this molecular event. Experimental Design: Archival tissue from lymphadenectomy specimens among patients (n = 136) with stage IIIB or IIIC melanoma was assessed by DNA sequencing for activating BRAF and NRAS mutations, and by immunohistochemistry for the expression of PTEN protein. Associations of these molecular aberrations with demographics, tumor characteristics, and clinical outcomes were determined. Results: The prevalence of BRAFV600 mutations (40% overall), NRAS mutations (10%), and PTEN loss (25%) did not vary by pathologic substage. BRAF/NRAS mutation status did not correlate with distant disease-free survival (DDFS) or overall survival (OS). Complete loss of PTEN expression correlated with shorter OS but not DDFS. When stratified by specific sites of distant metastasis, PTEN loss was associated with significantly shorter time to melanoma brain metastasis (MBM), but not to liver, lung, or bone metastasis. Analysis of PTEN in mutationally defined subsets showed that PTEN loss was significantly associated with OS and time to MBM in patients with BRAFV600 mutations. Conclusions: Loss of PTEN protein expression correlates significantly with decreased OS and time to MBM in stage IIIB/C melanoma patients with BRAFV600 mutations. The findings add to evidence supporting a significant role for PTEN loss and the PI3K–AKT pathway in melanoma. Clin Cancer Res; 20(21); 5527–36. ©2014 AACR.Keywords
Other Versions
This publication has 44 references indexed in Scilit:
- Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencingLaboratory Investigation, 2012
- Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAFOncogene, 2011
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationNew England Journal of Medicine, 2011
- BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor sitePigment Cell & Melanoma Research, 2011
- Determinants of survival in patients with brain metastases from cutaneous melanomaBritish Journal of Cancer, 2010
- AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human CancerCancer Cell, 2009
- BrafV600E cooperates with Pten loss to induce metastatic melanomaNature Genetics, 2009
- Mutations of the BRAF gene in human cancerNature, 2002
- Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancersNature Genetics, 1997
- PTEN , a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate CancerScience, 1997