Methods for predicting risk of metastasis in cutaneous melanoma

Abstract

The invention as disclosed herein in encompasses a method for predicting the risk of metastasis of a primary cutaneous melanoma tumor, the method encompassing measuring the gene-expression levels of at least eight genes selected from a specific gene set in a sample taken from the primary cutaneous melanoma tumor; determining a gene-expression profile signature from the gene expression levels of the at least eight genes; comparing the gene-expression profile to the gene-expression profile of a predictive training set; and providing an indication as to whether the primary cutaneous melanoma tumor is a certain class of metastasis or treatment risk when the gene expression profile indicates that expression levels of at least eight genes are altered in a predictive manner as compared to the gene expression profile of the predictive training set.

What is claimed is: 
     
         1 . A method for predicting risk of metastasis, overall survival, or both, in a patient with a primary cutaneous melanoma tumor, the method comprising:
 (a) measuring gene expression levels of at least eight genes selected from the group consisting of BAP1_varA, BAP1_varB, MGP, SPP1, CXCL14, CLCA2, S100A8, BTG1, SAP130, ARG1, KRT6B, GJA, ID2, EIF1B, S100A9, CRABP2, KRT14, ROBOT, RBM23, TACSTD2, DSC1, SPRR1B, TRIM29, AQP3, TYRP1, PPL, LTA4H, and CST6, in a sample of the primary cutaneous melanoma tumor, wherein measuring gene expression levels of the at least eight genes comprises measurement of a level of fluorescence by a sequence detection system following RT-PCR of the at least eight genes;   (b) determining a patient gene-expression profile signature comprising the gene expression levels of the at least eight genes;   (c) comparing the patient gene-expression profile signature to a gene-expression profile of a predictive training set; and   (d) providing an indication as to a risk of metastasis, overall survival or both for the primary cutaneous melanoma tumor when the patient gene expression profile indicates that the expression levels of at the least eight genes are altered in a predictive manner as compared to the gene expression profile of the predictive training set.   
     
     
         2 . The method of  claim 1 , wherein the risk of metastasis for the primary cutaneous melanoma tumor is classified from a low risk of metastasis to a high risk of metastasis. 
     
     
         3 . The method of  claim 2 , wherein class 1 indicates a low risk of metastasis, class 2 indicates a high risk of metastasis, class A indicates a low risk of metastasis, class B indicates an intermediate risk of metastasis and class C indicates a high risk of metastasis. 
     
     
         4 . The method of  claim 1 , further comprising determining that the primary cutaneous melanoma tumor has an increased risk of metastasis or decreased overall survival by combining with at least one of TNM (Tumor-Node-Metastasis) status, clinical staging set by American Joint Committee on Cancer (AJCC) to stage the primary cutaneous melanoma tumor, and sentinel lymph node biopsy status. 
     
     
         5 . The method of  claim 1 , wherein a sentinel lymph node biopsy was performed in the patient from which the primary cutaneous melanoma tumor was separately obtained. 
     
     
         6 . The method of  claim 5 , wherein the sentinel lymph node biopsy was negative. 
     
     
         7 . The method of  claim 1 , wherein the at least eight genes are KRT6B, GJA1, AQP3, TRIM29, TYRP1, RBM23, MGP and EIF1B. 
     
     
         8 . The method of  claim 1 , wherein the at least eight genes are SAP130, ARG1, KRT6B, EIF1B, S100A9, KRT14, ROBOT, RBM23, TRIM29, AQP3, TYRP1 and CST6. 
     
     
         9 . The method of  claim 1 , wherein the at least eight genes are GJA1, PPL, ROBOT, MGP, TRIM29, AQP3, RBM23, TACSTD2, TYRP1, KRT6B, EIF1B and DSC1. 
     
     
         10 . The method of  claim 1 , wherein the at least eight genes are CRABP2, TYRP1, PPL, EIF1B, SPRR1B, DSC1, GJA1, AQP3, MGP, RBM23, CLCA2 and TRIM29. 
     
     
         11 . The method of  claim 1 , wherein the at least eight genes are RBM23, TACSTD2, CRABP2, PPL, GJA1, SPP1, CXCL14, EIF1B, AQP3, MGP, LTA4H and KRT6B. 
     
     
         12 . The method of  claim 1 , wherein the at least eight genes are S100A8, TACSTD2, BAP1_varA, KRT6B, EIF1B, TRIM29, TYRP1, CST6, PPL, RBM23, AQP3, GJA1, SPRR1B and ARG1. 
     
     
         13 . The method of  claim 1 , wherein the at least eight genes are CST6, KRT6B, LTA4H, CLCA2, CRABP2, TRIM29, CXCL14, PPL, ARG1, RBM23, GJA1, AQP3, TYRP1, SPP1, DSC1, TACSTD2, EIF1B, and BAP1_varA. 
     
     
         14 . The method of  claim 1 , wherein the primary cutaneous melanoma tumor is taken from a formalin-fixed, paraffin embedded wide local excision sample. 
     
     
         15 . The method of  claim 1 , wherein the primary cutaneous melanoma tumor is taken from formalin-fixed, paraffin embedded biopsy sample selected from a punch biopsy, a shave biopsy and another biopsy method. 
     
     
         16 . A method of treating cutaneous melanoma in a patient, the method comprising:
 (a) measuring gene expression levels of at least eight genes selected from the group consisting of BAP1_varA, BAP1_varB, MGP, SPP1, CXCL14, CLCA2, S100A8, BTG1, SAP130, ARG1, KRT6B, GJA, ID2, EIF1B, S100A9, CRABP2, KRT14, ROBOT, RBM23, TACSTD2, DSC1, SPRR1B, TRIM29, AQP3, TYRP1, PPL, LTA4H, and CST6 in a sample of a primary cutaneous melanoma tumor in the patient, wherein measuring gene expression levels of the at least eight genes comprises determining a level of fluorescence by a sequence detection system following RT-PCR of the at least eight genes;   (b) determining a patient gene-expression profile signature comprising the gene expression levels of the at least eight genes;   (c) comparing the patient gene-expression profile signature to a gene-expression profile of a predictive training set;   (d) making a determination as to whether the patient gene-expression profile signature of the at least eight genes is altered in a predictive manner; and   (e) administering an aggressive cancer treatment regimen to the patient when the determination is made in the affirmative that the patient has a primary cutaneous melanoma tumor with an increased risk of metastasis or decreased overall survival.   
     
     
         17 . A method of treating cutaneous melanoma in a patient, the method comprising:
 (a) measuring gene expression levels of at least eight genes selected from the group consisting of BAP1_varA, BAP1_varB, MGP, SPP1, CXCL14, CLCA2, S100A8, BTG1, SAP130, ARG1, KRT6B, GJA, ID2, EIF1B, S100A9, CRABP2, KRT14, ROBOT, RBM23, TACSTD2, DSC1, SPRR1B, TRIM29, AQP3, TYRP1, PPL, LTA4H, and CST6 in a sample of a primary cutaneous melanoma tumor in the patient, wherein measuring gene expression levels of the at least eight genes comprises determining a level of fluorescence by a sequence detection system following RT-PCR of the at least eight genes;   (b) determining a patient gene-expression profile signature comprising the gene expression levels of the at least eight genes;   (c) comparing the patient gene-expression profile signature to a gene-expression profile of a predictive training set;   (d) making a determination as to whether the patient gene-expression profile signature of the at least eight genes is altered in a predictive manner; and   (e) performing a sentinel lymph node biopsy (SLNB) on the patient when the determination is made in the affirmative that the patient has a primary cutaneous melanoma tumor with an increased risk of metastasis or decreased overall survival.   
     
     
         18 . The method of  claim 17 , further comprising determining that the primary cutaneous melanoma tumor has an increased risk of metastasis or decreased overall survival by combining with TNM status, AJCC clinical staging to stage the primary cutaneous melanoma tumor, or both.