Breakthroughs in understanding the genetic basis of aggressive prostate cancer

December 6, 2017
This plot represents a circularized version of the human genome. Each subsequent inner ring represents novel findings in the study relevant to disease. Credit: Christopher McNair, Thomas Jefferson University

The retinoblastoma (RB) susceptibility gene was the first gatekeeper gene discovered for cancer. When it was removed, or damaged, cancers thrived. Over the years, researchers discovered many methods to experimentally remove the RB gene in order to study it, but just how the gene's loss made cancers more aggressive in patients was poorly understood. By studying patient samples, researchers at Thomas Jefferson University and colleagues found how one type of RB removal, but not another, caused large-scale genetic changes that could make cancer both resistant to treatment and more likely to spread.

"RB loss causes a major reprogramming of gene expression, allowing induction of pathways that promote features that induce characteristics of lethal disease," said senior author Karen Knudsen, PhD, Director of the Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University. The study is the first to identify the molecular consequences of RB loss and illustrate the clinical relevance of RB-loss-induced transcriptional rewiring.

The work involved a multinational collaboration between SKCC investigators at Thomas Jefferson University and other US-based laboratories, as well as clinical and basic science researchers in the UK, Italy, Belgium, Finland and Sweden. It was published online December 4th in The Journal of Clinical Investigation.

Spearheaded by first author Christopher McNair, PhD, a graduate student in the laboratory of Dr. Knudsen, the study undertook an extensive analysis of tumor samples and cell-free DNA samples from with advanced, lethal-stage . Although there are several ways to remove RB from the cellular machinery, the group found that complete loss, rather than inactivation, of the RB gene was associated with changes in gene-networks closely linked to aggressive disease. Surprisingly, the -promoting program that RB-loss unleashed was distinct from the cell-cycle control that RB is best known for controlling.

The new findings hold great promise for further clinical development and application. First, the research demonstrates that RB status can be tracked using cell-free DNA samples, an approach referred to as "liquid biopsy", in prostate cancer patient samples. This method will facilitate the analysis of patient tumors and the selection of the most appropriate therapy based on the individualized features of each patient's cancer subtype. Multiple clinical trials are now underway in Philadelphia that will determine the impact of RB status as a means to guide more precise cancer therapy. "Unlike breast cancer, all prostate cancers are currently treated in an identical fashion. This discovery, and the clinical trials we have underway, suggest that RB status might be used as means to stratify patients into more effective treatment regimens," said William Kevin Kelly, leader of the Prostate Cancer Program at SKCC.

Explore further: Common genetic fusion event may be associated with low-risk prostate cancer

More information: Christopher McNair et al, Differential impact of RB status on E2F1 reprogramming in human cancer, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI93566

Related Stories

Common genetic fusion event may be associated with low-risk prostate cancer

November 10, 2017
Establishing the way in which a genetic alteration called a TMPRSS2-ERG gene fusion forms in a prostate cancer, rather than the presence of the gene fusion itself, could help identify patients with prostate cancer with a ...

Decoding the molecular mechanisms of ovarian cancer progression

November 28, 2017
Ovarian cancer is the most lethal gynecologic malignancy in the United States, resulting in an estimated 14,100 deaths and 22,500 new cases in 2017 alone. This high mortality is primarily caused by resistance to therapy and ...

SABCS: Loss of RB in triple negative breast cancer associated with favorable clinical outcome

December 9, 2011
Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with ...

ONC201 may inhibit cancer stem cell self-renewals by altering their gene expression

August 2, 2017
ONC201 may inhibit cancer stem cell self-renewals by altering their gene expression, according to a study published August 2, 2017 in the open-access journal PLOS ONE by Varun Vijay Prabhu from Oncoceutics, Inc., USA and ...

Research helps explain why androgen-deprivation therapy doesn't work for many prostate cancers

January 5, 2017
Metastatic prostate cancer, or prostate cancer that has spread to other organs, is incurable. In new research published in the journal Science, Roswell Park Cancer Institute scientists have identified two gatekeeper genes ...

Sequencing prostate tumors from African-American men reveals a novel tumor suppressor gene

May 19, 2017
African-American men develop prostate cancer more often than other men, and it tends to be more deadly for this population. Some of the differences seem to be due to socioeconomic factors, but scientists wondered whether ...

Recommended for you

New strategy for unleashing cancer-fighting power of p53 gene

December 13, 2017
Tumor protein p53 is one of the most critical determinants of the fate of cancer cells, as it can determine whether a cell lives or dies in response to stress. In a new study published today in the journal Nature Communications, ...

Researchers develop test that can diagnose two cancer types

December 12, 2017
A blood test using infrared spectroscopy can be used to diagnose two types of cancer, lymphoma and melanoma, according to a study led by Georgia State University.

Cancer-causing mutation suppresses immune system around tumours

December 12, 2017
Mutations in 'Ras' genes, which drive 25% of human cancers by causing tumour cells to grow, multiply and spread, can also protect cancer cells from the immune system, finds a new study from the Francis Crick Institute and ...

Atoh1, a potential Achilles' heel of Sonic Hedgehog medulloblastoma

December 12, 2017
Medulloblastoma is the most common type of solid brain tumor in children. Current treatments offer limited success and may leave patients with severe neurological side effects, including psychiatric disorders, growth retardation ...

MRI scans predict patients' ability to fight the spread of cancer

December 12, 2017
A simple, non-invasive procedure that can indicate how long patients with cancer that has spread to the brain might survive and whether they are likely to respond to immunotherapy has been developed by researchers in Liverpool.

Drug suppresses spread of breast cancer caused by stem-like cells

December 12, 2017
Rare stem-like tumor cells play a critical role in the spread of breast cancer, but a vulnerability in the pathway that powers them offers a strategy to target these cells using existing drugs before metastatic disease occurs, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.