Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review

 Blogger's Note: 2nd link JNCI

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Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review:

Background
MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.

Methods
Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.

Results
Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34–129), the median number of miRs assayed was 328 (IQR = 250–470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26–5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).

Conclusions
MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias.

press release: Researchers discover a DNA marker (microRNA-16) that indicates if ovarian cancer treatment will be successful

Researchers discover a DNA marker that indicates if ovarian cancer treatment will be successful

Public release date: 3-Apr-2012

Researchers discover a DNA marker that indicates if ovarian cancer treatment will be successful

CHICAGO, IL – Researchers and doctors at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research have discovered that blood can help determine the best treatment plan for patients with ovarian cancer. More specifically, a genetic marker embedded in deoxyribonucleic acid (DNA), called microRNA, indicates if a patient with ovarian cancer has a benign or cancerous tumor, and that she will benefit from chemotherapy after surgery on the tumor. This data will be presented at the American Association for Cancer Research (AACR) Annual Meeting to be held from Saturday through Wednesday (March 31- April 4) in Chicago, IL.

It is estimated that there will be 22,280 new cases and 15,500 deaths this year from ovarian cancer in the United States. Due to lack of adequate screening, the majority of patients with ovarian cancer are diagnosed at stage III (the second-to-last and most devastating stage of cancer), when 70 percent of these patients will die of their disease within 5 years.

"The discovery that microRNAs can help predict the best treatment plan for women with ovarian cancer, who are most likely at stage III of the disease, offers them enormous hope," noted Iuliana Shapira, MD, director of the Cancer Genetics Program at the North Shore-LIJ Health System's Monter Cancer Center. "We can now inform patients at stage III ovarian cancer, if they will have success with chemotherapy following surgery, similar to patients who are at stage 1 disease. This information gives them hope that their disease is curable despite being diagnosed at an 'advanced stage.' It also gives them the strength necessary to undergo chemotherapy, which is a very invasive and toxic therapy necessary to obtain the cure." (Blogger's Note: a 'forward' looking statement; see text in red highlighted below)

Several microRNAs have been found to have links with various types of cancer. The research conducted at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research found that microRNA-195 increased 40 fold during chemotherapy and microRNA-16 increased 80 fold during chemotherapy. These changes may explain why some patients with ovarian cancer have side effects of chemotherapy, why others become cured of cancer as a result of chemotherapy, and why others need ongoing chemotherapy to continue living with the cancer.

"Understanding the changes in microRNA throughout chemotherapy treatment helps us better understand ovarian cancer and how best to treat patients who have this disease," said Annette Lee, PhD, associate investigator at the Feinstein Institute. "The genetic markers we identified allow patients to individualize their own therapy in order to have maximum benefit and minimal side effects. In addition, this knowledge will help researchers develop new treatments for patients with ovarian cancer."

Dr. Shapira adds that, "We applied for a government grant and hope to receive the funds needed to validate these markers allow result in women receiving therapies that are more personalized and match their genetic makeup."

open access: PLoS ONE: March 29th Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

PLoS ONE: Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

Background

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.

Conclusions

This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.

abstract: Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review

Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review

Background
MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.

. ........The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26–5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).

Conclusions MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias.

abstract: Evaluation of microRNA expression profiles and their associations with risk alleles in lymphoblastoid cell lines of familial ovarian cancer

Lymphoblast - Wikipedia, the free encyclopedia

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Lymphoblasts are immature cells which typically differentiate to form mature ... Although commonly lymphoblast refers to a precursor cell in the maturation of ...

SGO: MicroRNA May Help Predict Ovarian Ca Response - in Meeting Coverage, SGO from MedPage Today

"Changes in expression of a microRNA showed potential for predicting response to the angiogenesis inhibitor bevacizumab (Avastin) in recurrent serous ovarian cancer, according to results of a small study reported here..........."

abstract: A microRNA survival signature (MiSS) for advanced ovarian cancer (serous)

 Abstract

Objectives

MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer.

Results

Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49 ± 4 months. The training set identified 3 miRNAs associated with survival — miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR = 2.96, 95% CI: 1.51–5.78). This miRNA survival signature (MiSS) was validated in the test set (HR = 1.71, 95% CI: 1.05–2.78). The MiSS was independent of FIGO stage and surgical debulking.

Conclusions

The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms.

Research highlights

► A MicroRNA Survival Signature was developed in advanced ovarian carcinoma.
► The signature was independent of common clinical co-variates.

Commentary: microRNAs in stage I epithelial ovarian cancer : The Lancet Oncology

"In epithelial ovarian cancer (EOC), miRNA-expression profiles have been described that are associated with different characteristics of ovarian cancer (eg, tumour subtype, stage, histological grade, prognosis, and therapy resistance)........However, these studies should focus on pure histotypes, as EOC is thought to be a heterogeneous disease in which some histotypes are completely different entities all together, with different response outcomes to standard treatment. Another confounding factor for prognostic marker discovery might be exposure to platinum-based combination chemotherapy. Preferably, only patients who did not receive chemotherapy should be analysed for PFS. Because stage I EOC samples are relatively rare, we encourage additional studies to be done by international consortia. With the above-mentioned considerations in mind, valid miRNA biomarkers will be identified that can be of use in the clinic, and help to personalise treatment."

Scientists peer into the future of stem cell biology (microRNAs)

Baylor researchers advancing genetic treatment for ovarian cancer - Baylor College of Medicine press release - (microRNA - miR-31)

HOUSTON -- (September 16, 2010) -- As the understanding of the biology of ovarian cancer broadens, there is an increased need to develop treatments that are targeted toward a person's genetic makeup, said a clinician-researcher from Baylor College of Medicine.

"We have not been able to pinpoint exactly what causes ovarian cancer," said Dr. Matthew Anderson, assistant professor of obstetrics and gynecology and a member of the NCI-designated Dan L. Duncan Cancer Center at BCM. "However, we do know that the molecular changes in each ovarian cancer are different and each person's response to treatment is unique."

Anderson said a major research goal is to individualize treatments for each woman, so that clinicians are able to more effectively manage or perhaps even cure ovarian cancer.

That's why Anderson and his team, including Dr. Martin Matzuk, professor of pathology at BCM, and Dr. Preethi Gunaratne, assistant professor of pathology at BCM and assistant professor of biochemistry and biology at the University of Houston, are in the process of developing treatments that target the different types of molecular changes that they have identified as playing a role in ovarian cancer development.
Identifying new genetic signatures

Their work focuses on a class of recently discovered small non-coding RNA transcripts in ovarian cancer called microRNAs. MicroRNAs are tiny messenger molecules that are generated by chromosomes that feed back to inhibit the expression of traditional, protein-coding genes. They have become a hot topic in biology because an individual microRNA can target many hundreds of different genes, making them potentially very powerful as therapeutic or diagnostic targets, Anderson said.
"Genes have many signals and rules that turn them on and off," said Anderson. "MicroRNAs are one kind of signal. When these signals do not get turned on or off appropriately, gene expression is altered, causing changes in cell behavior that we now know can lead to cancer."

Using Next Generation Sequencing, Anderson and his colleagues identified a number of microRNAs, including miR-31, involved in ovarian cancer. In the case of miR-31, decreased levels were found in every ovarian cancer studied, potentially altering the expression of more than 2,200 individual gene products.

Their work has now been published in the American Association of Cancer Research journal Cancer Research. Anderson also received a basic science award from the Society of Gynecologic Oncologists for a presentation at its 41st Annual Meeting on Women's Cancer in March 2010.

Anderson and team hypothesize that a treatment targeting this malfunction could be effective against cancers that are shown to lack miR-31.

"In the lab, we have shown that once miR-31 is turned back on, cancer growth stops and the cells die," said Anderson.
Next step in research

The next question is finding out how miR-31 can be administered safely as a treatment in humans, Anderson said. "The process will start using ovarian cancer models and then move to human trials."

Another important question is how to determine which patients are likely to benefit from these treatments.
"Physicians understand that the same drug does not always work for the same problem in all people," said Anderson. "This is particularly true for cancer. Understanding how and when microRNAs stop cancer growth can help to tell us how this new class of targets can be used for different people and diseases."

"In the future, we particularly want to be able to take a tumor and comprehensively profile the genetic changes that are specific to the ovarian cancer for each women so that we can prospectively determine what treatment works best for each person," said Anderson. "We believe that this approach will generate far superior results than the currently 'one-size-fits-all' approach used to treat this disease."
Partnership for Baylor College of Medicine campaign

Anderson, Matzuk and Gunaratne's project was selected as the main fundraising effort for 2010-2011 by the Partnership for Baylor College of Medicine, the college's primary support group.

The group will focus their community advocacy, educational programs and involvement in fundraising activities on the project.

"Translating this finding into a clinical application is critically important," said Anderson. "The Partnership support will help us to advance this process significantly."

PLoS ONE: Repertoire of microRNAs in Epithelial Ovarian Cancer as Determined by Next Generation Sequencing of Small RNA cDNA Libraries

Note: full free access / technical

Background

MicroRNAs (miRNAs) are small regulatory RNAs that are implicated in cancer pathogenesis and have recently shown promise as blood-based biomarkers for cancer detection. Epithelial ovarian cancer is a deadly disease for which improved outcomes could be achieved by successful early detection and enhanced understanding of molecular pathogenesis that leads to improved therapies. A critical step toward these goals is to establish a comprehensive view of miRNAs expressed in epithelial ovarian cancer tissues as well as in normal ovarian surface epithelial cells.

Conclusions

This report expands the body of miRNAs known to be expressed in epithelial ovarian cancer and provides a useful resource for future studies of the role of miRNAs in the pathogenesis and early detection of ovarian cancer.

Discussion

The work reported here was motivated by the hypothesis that the entire repertoire of miRNAs expressed in ovarian cancer, including potentially tissue- and cancer-specific miRNAs, had not yet been elucidated.

abstract: miR-20a promotes proliferation and invasion by targeting APP in human ovarian cancer cells.

define: microRNA - A short piece of single-stranded RNA that does not encode a protein and controls the expression of genes.
Abstract:

MicroRNAs (miRNAs) are emerging as a class of small regulated RNAs, and the alterations of miRNAs are implicated in the initiation and progression of human cancers. Our study shows that inhibition of miR-20a in OVCAR3 ovarian cancer cell line could suppress, whereas overexpression of miR-20a could enhance cell long-term proliferation and invasion. We also confirmed amyloid precursor protein (APP) as a direct target gene of miR- 20a. Furthermore, suppression of APP expression could also promote ovarian cancer cell proliferation and invasion, which is consistent with the results of miR-20a overexpression. Therefore, we concluded that the regulation of APP is an important mechanism for miR-20a to promote proliferation and invasion in ovarian cancer cells.

The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment

Review

The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment

CCR Connections (News NIH) - Big Things in Small Packages: Small RNAs Play a Big Role in Cancer Biology

"Exquisitely tuned gene expression is essential to orchestrate both the development and functioning of the myriad cell types in the human body. When that tuning goes awry, one result is cancer. Small microRNAs (miRNAs) have emerged relatively recently as key modulators of gene expression, acting at a stage between transcription of the genes and translation into proteins. Although they are tiny, miRNAs—at a little over 20 nucleotides long—pack a big punch since each regulates a variety of genes, and they are involved in diverse pathological processes, including cell proliferation and death...."

In research: Scientists identify microRNA as possible cause of chemotherapy resistance

Public release date: 10-Mar-2010  AACR conference

Scientists identify microRNA as possible cause of chemotherapy resistance

DEAD SEA, Jordan — Scientists may have uncovered a mechanism for resistance to paclitaxel in ovarian cancer, microRNA-31, suggesting a possible therapeutic target for overcoming chemotherapy resistance.
Mohamed K. Hassan, Ph.D., a postdoctoral fellow at Hokkaido University in Japan, completed the research as a collaborative study with his colleagues when he was a professional assistant in South Valley University in Egypt. Results of this study were presented at the second AACR Dead Sea International Conference on Advances in Cancer Research: From the Laboratory to the Clinic, held March 7-10, 2010.

"MicroRNAs do not code protein, but they regulate other proteins' expression," said Hassan. "So identifying any microRNA as responsible for chemoresistance is, in fact, introducing a real reason for the mechanism."

Ovarian cancer is typically responsive to chemotherapy with paclitaxel, but sometimes cancer cell lines become resistant, which renders chemotherapy useless. Hassan's research team analyzed a set of microRNAs and identified microRNA-31 as being responsible for this chemoresistance. MicroRNA-31 regulates the protein IFITM-1.
"We need to further verify this observation in clinical ovarian cancer samples and find a way to inhibit this target protein to improve the effect of paclitaxel and prevent the risk of recurrence," he said.

Using microRNAs to understand cancer biology : The Lancet Oncology

"Studies such as that by Ueda and colleagues offer hope to patients with cancer that in the future they will be offered truly tailored treatment, based on the unique biology of their tumour as defined by microRNAs."
"This type of study needs to be done for every cancer type."

MicroRNAs in ovarian carcinomas -- Dahiya and Morin 17 (1): F77 -- Endocrine-Related Cancer

(abstract) FOCUS REVIEW
MicroRNAs in ovarian carcinomas
Neetu Dahiya1 and Patrice J Morin1,2
1 Laboratory of Cellular and Molecular Biology, National Institute on Aging, NIH Biomedical Research Center, 251 Bayview Boulevard, Suite 100, Room 6C228, Baltimore, Maryland 21224, USA
2 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA