Addressing the Elephant in the Room in Cancer Genetic

Researchers from Harvard Medical School have predicted that many more tumor suppressor and oncogenes have a combined effect on the development of disease than originally thought, concluding that cancer is even more complex than imagined.

In a paper published last month in the journal Cell, the team—led by Medical School professor of genetics Stephen J. Elledge—addressed the impact of aneuploidy, an extra or missing chromosome in an individual’s cells, on cancer development.

While aneuploidy is a very common abnormality, most aneuploidies are lethal.

Aneuploidy has been observed in cancer patients for a while, but Elledge said that “aneuploidy was the elephant in the room.” He explained that the oncogene revolution brought point mutations to the attention of scientists and research has been focused on simpler targets in the last several decades.

Using a computational method that they devised, Elledge’s team analyzed mutations in tumors for tumor suppressor genes and oncogenes to identify mutation patterns that give rise to an oncogenic state.

The paper, titled “Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome,” reported that many more factors can drive the development of cancer, such as avoiding apoptosis, or programmed cell death, escaping immune response, avoiding differentiation, and sustaining proliferation.

In addition, the researchers found that contribution of weak drivers can sum up to correspond to the effect of a more potent driver.

“People always knew cancer chromosomes were a big mess, but they didn't know how much of this mess was important,” Elledge said.

The findings also suggest that the “Two-Hit” hypothesis, a central view on tumor suppression proposed by the geneticist Alfred G. Knudson, might have been generalized to make sporadic cancers appear simpler than they actually are.

According to the “Two-Hit” model, the first hit is not enough to contribute to the formation of a tumor in familial cancers, but mutations to the second copy of the same chromosome were thought to provide the second hit that drives the development of tumors.

In the study, scientists suggest that most tumor suppressor genes may be haploinsufficient  in sporadic cancers, meaning that one copy of the gene is not fully functional anyway. If that is the case, the second hit might not be necessary to cause tumor development.

Elledge added that the next step is to engineer deletion and amplifications to recreate the events that occur in cancer cells.