Expression protein-coding and noncoding genes as prognostic classifiers in early stage lung cancer
Inventors
Harris, Curtis C. • Schetter, Aaron Joseph • Okayama, Hirokazu • Akagi, Ichiro
Assignees
US Department of Health and Human Services
Publication Number
US-10047401-B2
Publication Date
2018-08-14
Expiration Date
2033-08-20
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Abstract
The invention provides novel biomarkers (four genes BRCA1, HIF1A, DLC1, and XPO1 alone or in combination of miR-21) for early stage lung cancer.
Core Innovation
The invention provides novel biomarkers comprising four genes BRCA1, HIF1A, DLC1, and XPO1 alone or in combination with miR-21 for early stage lung cancer. It offers methods for determining prognosis, diagnosing risk, predicting recurrence, and selecting appropriate therapy for subjects with lung cancer by detecting the levels of these biomarkers in samples from the subject and comparing them to reference levels from healthy controls.
The problem being solved arises in stage I non-small cell lung cancer (NSCLC) patients, where surgery with curative intent is standard, but 20-30% will experience recurrence even after successful surgery and negative lymph nodes. The benefit of adjuvant chemotherapy in stage I patients is controversial. There is a need for biomarkers that can identify stage I lung cancer patients at high risk of recurrence who may benefit from adjuvant therapy.
The invention further provides a molecular classifier that stratifies early stage lung cancer patients across diverse populations to reliably identify those at high risk for disease progression. This classifier may aid clinical decisions by helping to choose appropriate therapeutic pathways. Methods involve detecting expression levels of BRCA1, HIF1A, DLC1, XPO1, and optionally miR-21, comparing expression to a reference, and identifying increased expression levels of BRCA1, HIF1A, XPO1, and miR-21 or decreased DLC1 as indicators of adverse prognosis or at risk status.
Claims Coverage
The patent contains two independent claims covering a method of detecting specific gene expression levels in a subject's lung tissue sample.
Simultaneous detection of mRNA levels of BRCA1, HIF1A, DLC1, and XPO1 in a lung RNA sample
A method comprising contacting an RNA sample from the subject's lung with probes specific for BRCA1, HIF1A, DLC1, and XPO1 mRNA and detecting binding to determine their expression levels.
Detection of miR-21 levels in the sample
A method comprising contacting the same sample with a probe specific for miR-21 and detecting binding to determine its expression level.
Use of specific detection techniques for mRNA levels
The method wherein the mRNA levels of the four genes are detected by microarray, RT-PCR, qRT-PCR, nanostring assay, or in situ hybridization.
The claims cover methods for detecting expression levels of four protein-coding genes and a noncoding microRNA (miR-21) in lung samples using molecular probes and standard molecular techniques, enabling prognosis and diagnosis in lung cancer patients.
Stated Advantages
Provides novel biomarkers that reliably identify early stage lung cancer patients at high risk of disease progression.
Enables stratification of diverse patient populations to guide therapeutic decisions and improve post-operative care.
Improves prediction of lung cancer prognosis, risk of recurrence, and selection of appropriate therapy over existing methods.
Combination of the four gene classifier with miR-21 expression enhances prognostic accuracy.
Documented Applications
Diagnosis of early stage lung adenocarcinoma and identification of patients at high risk of recurrence.
Determining prognosis of subjects with lung cancer including risk of developing lung cancer and risk of recurrence.
Selecting appropriate therapy, including adjuvant chemotherapy and radiotherapy, for lung cancer patients based on biomarker expression.
Assigning patients to closer follow-up, more frequent screenings, or clinical trials based on biomarker levels.
Use in diagnostic kits containing reagents for detecting BRCA1, HIF1A, DLC1, XPO1, and miR-21 for aiding diagnosis and treatment decisions in lung cancer.
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