Aneuploidy in Cancer: A Long-Standing Debate
The vast majority of cancer cells exhibit either a deficit or an excess of certain chromosomes, a condition known as aneuploidy. Since its discovery in the late 19th century, researchers have debated whether aneuploidy actively fuels cancer or is merely a byproduct of the rapid growth of cancer cells.
Challenges in Studying Aneuploidy
Studying DNA changes on such a large scale has proven challenging. However, a recent study published in Nature confirms that aneuploidy indeed plays a significant role in cancer development, thanks to a novel computational tool.
A Breakthrough with BISCUT
On June 28, 2023, researchers at the Broad Institute published a groundbreaking research paper titled “Cancer Aneuploidies are Primarily Shaped by Effects on Tumor Fitness”. The research team devised a computational method called BISCUT, which compares chromosomal changes in tumor cells from over 10,000 cancer patients. The study concludes that chromosomal aneuploidy is highly prevalent in cancer due to selection, rather than occurring coincidentally.
Key Findings and New Insights
Utilizing BISCUT, the study also identified crucial chromosomal regions that are either missing or duplicated in aneuploidy, affecting tumor cells either detrimentally or advantageously. Additionally, the study shed light on a novel role for a known oncogene called WRN. These findings open up new avenues for guiding cancer treatment and the development of targeted drugs.
Implications of Aneuploidy in Cancer
Rameen Beroukhim, the corresponding author of the paper, stated, “By utilizing tumor samples directly from cancer patients, our study provides a computationally derived answer to the age-old question of aneuploidy—whether these large-scale chromosomal events drive cancer or are merely coincidental in cancer development. The results clearly demonstrate that the impact of aneuploidies on cancer is determined by their effects on cancer cells, whether they are harmful or beneficial.”
Historical Context of Aneuploidy
While human cells normally possess 23 pairs of chromosomes, scientists in the late 19th century noticed that tumor cells often displayed abnormal chromosome numbers. Recent studies have revealed that aneuploidy, encompassing duplications or deletions of entire chromosome arms, is present in approximately 90% of human cancers. Moreover, aneuploidy typically emerges early in the cancer process and is associated with poorer clinical outcomes.
The Need for Further Research
For over a century, scientists have recognized the prominence of aneuploidies in the cancer genome. However, effective means of studying them have been lacking.
Investigating Chromosomal Changes
To investigate aneuploidy in cancer, the research team aimed to determine if other smaller-scale chromosomal changes in cancer cells could help identify the specific chromosome regions that play a role in tumor growth and survival.
The Role of BISCUT in Cancer Research
In their latest study, the team developed a new method, Breakpoint Identification of Significant Cancer Undiscovered Targets (BISCUT), to analyze the chromosomes most likely to undergo large-scale changes.
Selection Pressure and Survival
Using data from The Cancer Genome Atlas (TCGA), the research team analyzed 10,872 tumor samples representing 33 cancer types using BISCUT. The analysis revealed that cancer cells appeared to select for or against 193 regions within or near aneuploidy, with less than half of these regions containing known oncogenes.
New Paths in Cancer Treatment
Certain types of cancer heavily depend on the WRN gene, and research has been underway to develop drugs targeting this gene. However, this new study demonstrates that in up to one-third of cancers, the partial deletion of the WRN gene appears to contribute to the survival of cancer cells.
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