Clusters of cooperating tumor-suppressor genes are found in large regions deleted in common cancers
Scientists at Cold Spring Harbor Laboratory (CSHL) and Memorial Sloan-Kettering Cancer Center have amassed strong experimental evidence implying that commonly occurring large chromosomal deletions that are seen in many cancer types contain areas harboring multiple functionally linked genes whose loss, they posit, confers a survival advantage on growing tumors.
Looking closely at one large deletion -- a so-called copy-number alteration or CNA on 8p, the short arm of chromosome 8 -- in mouse models of human liver cancer, the team validated the presence of a number of genes which normally serve to suppress the formation of tumors, and demonstrated that they act together, and not singly, to suppress tumors. The 8p deletion is commonly seen in human liver cancer and in other epithelial cancers including those of the breast, colon and lung.
The research team, which was co-led by now-adjunct CSHL Professor Scott W. Lowe of Memorial Sloan-Kettering Cancer Center and CSHL Professor Michael Wigler, publishes their results online today in Proceedings of the National Academy of Sciences.
Their hypothesis about the relation between linked tumor suppressor genes in CNAs and tumor survival advantage, if validated in ongoing research, would significantly modify a popular theory of cancer genetics that has stood up since the 1970s. Called the "two-hit" hypothesis, it has helped to explain the behavior of certain cancer genes. All cancers arise from mutations in cancer genes that balance cellular proliferation and suppression of abnormal growth, resulting in out-of-control proliferation, cancer's hallmark.
Some cancers are the result of a single genetic "hit." An example is a single point mutation in the first human oncogene ever discovered, called RAS. It results in the production of an abnormal protein that drives cells to bypass growth checkpoints. The 2-hit hypothesis was proposed to explain aspects of a childhood eye cancer called retinoblastoma. Children with the inherited disease developed the disease early --- often in both eyes, whereas children who had the non-inherited, or sporadic form of the disease, developed it later and usually in one eye. It turned out that the inherited disease was caused by a recessive mutation in a single gene called RB1 but that the remaining, normal copy of the gene had to be lost in order for the disease process to begin. (We have two copies of most genes, one inherited from each parent.) The sporadic, non-inherited form of the disease required two hits of the RB1 gene, one of which was loss of a large region containing the gene.
This 2-hit model, which brilliantly explained retinoblastoma and some other cancers, "has also been used to explain what happens when all large chromosomal areas are lost in cancer something that happens quite frequently," notes Associate Professor Scott Powers, a CSHL geneticist and participant in the research published today.
"But the theory can't explain many of these large deletion events, for several reasons," Powers explains. "Most important, the deleted region often does not appear to contain a 'driver' tumor suppressor gene [like RB1] with a point mutation that would constitute the first 'hit.'" Lowe's lab at CSHL used the common 8p deletion to explore in mouse models of liver cancer what might be going on. Specifically, they asked a classic question in cancer: What selective advantage does the 8p deletion provide to the tumor?
In other words, when the 8p deletion occurs, how is a tumor's development aided? What new advantage do the affected cancer cells obtain?
The team found multiple genes within 8p and in adjacent areas of chromosome 8 that function cooperatively to inhibit the formation of tumors. They used RNA interference technology to show that the co-suppression of these linked sets of genes could "synergistically promote tumor growth."
These results "raise the possibility that large-scale genomic lesions can act through their effects on an opportunistic collection of linked genes rather than through disruption of a single resident gene," says CSHL Professor Michael Wigler, a pioneer in cancer genetics who participated in the research.
"The fact that the genes in 8p can cooperate to suppress tumor formation implies that the concomitant loss of multiple genes may create unexpected vulnerabilities not easily revealed through the study of single genes," states Dr. Lowe.
More information: "A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions" by Wen Xue et al., appears online May 7, 2012 in Proceedings of the National Academy of Sciences.
Journal reference: Proceedings of the National Academy of Sciences
Provided by Cold Spring Harbor Laboratory
- CSHL researchers discover three new genes that cause lung cancer Oct 08, 2007 | not rated yet | 0
- Scientists trace causal link between a tumor suppressor gene and liver cancer Jun 03, 2008 | not rated yet | 0
- By combining technologies, researchers rapidly hunt down and find new genes that lead to cancer Nov 13, 2008 | not rated yet | 0
- Scientists discover new gene that prevents multiple types of cancer Feb 09, 2007 | not rated yet | 0
- Study identifies therapeutic target for liver cancer and predictive biomarker of response Mar 14, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer May 19, 2013 | not rated yet | 0
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
Cancer May 19, 2013 | not rated yet | 1
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
Cancer May 18, 2013 | 5 / 5 (2) | 0
(HealthDay)—Concurrent use of two immune checkpoint antibodies—ipilimumab and nivolumab—may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in ...
Cancer May 17, 2013 | not rated yet | 0
(HealthDay)—The risks of metastasis and death associated with cutaneous squamous cell carcinoma (CSCC) are low, but significant, and risk factors for poor outcome include tumor diameter, invasion beyond ...
Cancer May 17, 2013 | not rated yet | 0 |
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, ...
13 hours ago | 4.8 / 5 (5) | 0 |
In their quest to learn more about the variability of cells between and within tissues, biomedical scientists have devised tools capable of simultaneously measuring dozens of characteristics of individual ...
13 hours ago | 5 / 5 (3) | 0 |
Researchers at the University of Wisconsin have identified a potential new risk factor for obstructive sleep apnea: asthma. Using data from the National Institutes of Health (Heart, Lung, and Blood Institute)-funded Wisconsin ...
12 hours ago | 5 / 5 (1) | 0 |
A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer's disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.
12 hours ago | 5 / 5 (2) | 0 |
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
17 hours ago | not rated yet | 0
Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the ...
12 hours ago | 5 / 5 (1) | 0