Molecular malignancy in melanocytic lesions

Inventors

Wang, Hui • Roberts, Christopher • Maddula, Krishna • Lu, Zhenquiang • Vasicek, Tom • Kerns, B J • SELIGMANN, BRUCE E. • Hoon, Dave S. B.

Assignees

John Wayne Cancer Institute • HTG Molecular Diagnostics Inc

Abstract

Disclosed are methods for determining whether a melanocyte-containing sample (such as a nevus or other pigmented lesion) is benign or a primary melanoma. These methods can include detecting (at the molecular level, e.g., mRNA, miRNA, or protein) the expression of at least two disclosed genes in a biological sample obtained from a subject. Also provided are arrays and kits that can be used with the methods.

Core Innovation

The invention distinguishes benign melanocytic nevi from primary melanoma and addresses indeterminant or atypical nevi in a subject by measuring nucleic acid expression in a nevi biopsy sample. Biomarkers comprising MAGEA2, PRAME, PDIA4, NR4A1, PDLIM7, B4GALT1, SAT1, RUNX1, and SOCS3 are measured, together with at least one normalization biomarker(s), to generate raw expression values for each biomarker.

Raw expression values for each biomarker are normalized to the raw expression values of the at least one normalization biomarker(s) to generate normalized expression values. Normalized expression values are used in a regression or machine learning algorithm to generate an output value, and the output value is compared by measuring an output value on a same side of a cut-off value as a plurality of known malignant melanoma samples, thereby enabling a classification decision for indeterminant or atypical nevi.

The invention further includes the clinical treatment step performed based on the classification output, by administering one or more chemotherapeutic agents, immunotherapy, or radiation therapy, performing additional surgery to remove lymph nodes or more tissue, or combinations thereof, to treat the indeterminant or atypical nevi in the subject. Documented implementations include nuclease protection assay approaches such as quantitative nuclease protection assay (qNPA) and nuclease protection probe (NPP), together with array and kit formats and use of FFPE tissue in an example gene discovery workflow.

Claims Coverage

The independent claim covers a combined diagnostic-and-treatment method with five core inventive features: measuring specified melanoma-related biomarkers plus normalization biomarkers, normalizing raw expression values, using normalized values in a regression or machine learning algorithm to generate an output value, classifying by comparison to a malignant melanoma cut-off, and administering therapy or additional surgery based on the classification result.

Across the independent claim, the inventive concept is a nucleic-acid expression profiling workflow that includes normalization, a regression or machine learning model producing an output value, a cut-off comparison relative to known malignant melanoma samples, and a treatment/surgery response to treat indeterminant or atypical nevi.

Stated Advantages

Documented Applications