Gene signature for predicting prognosis of patients with solid tumors
Inventors
Wang, Xin Wei • Roessler, Stephanie K.
Assignees
US Department of Health and Human Services
Publication Number
US-9394358-B2
Publication Date
2016-07-19
Expiration Date
2029-11-10
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Abstract
Disclosed herein is a driver gene signature for predicting survival in patients with solid tumors, such as hepatocellular carcinoma (HCC) and breast cancer. The gene signature includes ten tumor-associated genes, SH2D4A, CCDC25, ELP3, DLC1, PROSC, SORBS3, HNRPD, PAQR3, PHF17 and DCK. A decrease in DNA copy number or mRNA expression of SH2D4A, CCDC25, ELP3, DLC1, PROSC and SORBS3 in solid tumors is associated with a poor prognosis, while a decrease in DNA copy number or mRNA expression of HNRPD, PAQR3, PHF17 and DCK in solid tumors is associated with a good prognosis. Methods of predicting the prognosis of a patient diagnosed with HCC or breast cancer by detecting expression of one of more tumor-associated genes, and methods of treating a patient diagnosed with HCC or breast cancer by administering an agent that alters expression or activity of one or more of the disclosed tumor-associated genes, are described.
Core Innovation
The invention discloses a driver gene signature comprising ten tumor-associated genes—SH2D4A, CCDC25, ELP3, DLC1, PROSC, SORBS3, HNRPD, PAQR3, PHF17, and DCK—for predicting survival prognosis in patients with solid tumors, specifically hepatocellular carcinoma (HCC) and breast cancer. This gene signature is based on the observation that decreases in DNA copy number or mRNA expression of SH2D4A, CCDC25, ELP3, DLC1, PROSC, and SORBS3 are linked to poor prognosis, whereas decreases in DNA copy number or mRNA expression of HNRPD, PAQR3, PHF17, and DCK correspond to good prognosis.
This approach leads to the identification of a unique 10-gene signature predictive of clinical outcome in solid tumors such as HCC and breast cancer. The signature categorizes genes located on chromosomal loss regions; six genes on 8p associate with poor prognosis, and four genes on 4q associate with good prognosis. The signature enables prognostication as well as identification of potential therapeutic targets for drug development aimed at improving survival and preventing relapse or metastasis.
Claims Coverage
There are two independent inventive features focused on methods of treating hepatocellular carcinoma (HCC) with isolated nucleic acid molecules encoding specific tumor-associated genes.
Method of treating HCC by administering isolated nucleic acid encoding SH2D4A or SORBS3
A method comprising administering a therapeutically effective amount of an isolated nucleic acid molecule encoding one of the tumor-associated genes SH2D4A or SORBS3 to a subject with HCC, wherein the nucleic acid molecule is administered intratumorally.
Use of expression vectors encoding SH2D4A or SORBS3 for treatment of HCC
A method comprising administering a therapeutically effective amount of a vector comprising a nucleic acid molecule encoding SH2D4A or SORBS3 operably linked to a promoter to a subject with HCC, wherein the vector is administered intratumorally.
The claims cover methods of treating HCC by intratumoral administration of isolated nucleic acid molecules or vectors encoding the tumor-associated genes SH2D4A or SORBS3, emphasizing gene therapy approaches for modulating gene expression in solid tumors.
Stated Advantages
The 10-gene driver signature serves as an independent and significant predictor of survival for patients with hepatocellular carcinoma and breast cancer with mixed node status.
The identification of tumor suppressor genes SH2D4A and SORBS3 provides novel targets for genotype-specific treatment of solid tumors.
The gene signature enables distinction between functionally important driver mutations and passenger mutations in genomically unstable, heterogeneous solid tumors, improving prognostic accuracy and therapeutic strategies.
Documented Applications
Predicting prognosis of patients diagnosed with hepatocellular carcinoma by detecting expression or DNA copy number of two or more tumor-associated genes from the disclosed 10-gene signature in tumor samples compared to controls.
Predicting prognosis of patients diagnosed with breast cancer, especially with mixed node status, by detecting expression of two or more tumor-associated genes from the 10-gene signature.
Treating hepatocellular carcinoma or breast cancer by administering agents that alter expression or activity of one or more of the tumor-associated molecules, including methods employing isolated nucleic acid molecules encoding SH2D4A or SORBS3.
Identifying therapeutic agents that modulate expression or activity of the 10 tumor-associated genes for use in treatment of solid tumors.
Using arrays comprising probes or antibodies specific for two or more tumor-associated genes or proteins from the 10-gene signature for prognostic and diagnostic purposes in solid tumors.
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