Clusters of cooperating tumor-suppressor genes are found in large regions deleted in common cancers

May 7, 2012, Cold Spring Harbor Laboratory

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 , 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 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 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 in the first human oncogene ever discovered, called RAS. It results in the production of an that drives cells to bypass growth checkpoints. The 2-hit hypothesis was proposed to explain aspects of a childhood 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 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 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 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 ," 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.

Related Stories

Recommended for you

Single blood test screens for eight cancer types

January 18, 2018
Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

Researchers find a way to 'starve' cancer

January 18, 2018
Researchers at Vanderbilt University Medical Center (VUMC) have demonstrated for the first time that it is possible to starve a tumor and stop its growth with a newly discovered small compound that blocks uptake of the vital ...

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

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.