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.
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.
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.
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.
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.”
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.
Some researchers speculate that aneuploidy arises due to severe dysregulation of cancer cells and might not exert any significant effect on cancer. Identifying the molecular mechanisms through which aneuploidy influences tumor growth has been challenging, as the regions of DNA affected by aneuploidy can encompass hundreds or even thousands of genes.
For over a century, scientists have recognized the prominence of aneuploidies in the cancer genome. However, effective means of studying them have been lacking.
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. Although large-scale changes on chromosomes do not precisely align with the classical definition of aneuploidy, they do impact a significant portion of chromosome arms. These relatively short chromosome changes reveal whether cancer cells selectively undergo certain chromosome alterations.
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. If the starting and ending points were entirely random, it would suggest that aneuploidy has no direct effect on cancer cell survival. However, if a specific region frequently appears in the large-scale chromosomal changes, it implies that aneuploidy in that region contributes to cancer cell survival. Conversely, if a region is frequently excluded, it suggests that aneuploidy around that region kills cancer cells or hinders their growth.
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. Furthermore, the study found that the frequency of aneuploidy in different chromosomes correlated with the predicted selection pressure for aneuploidy regions.
Rameen Beroukhim emphasized that these results make it abundantly clear that selection plays a significant role in shaping aneuploidy patterns, and consequently, aneuploidy profoundly affects the survival of cancer cells.
Nearly one-third of the cancers documented in the TCGA database exhibit a deletion of one arm of chromosome 8, yet previous studies have failed to determine why this aneuploidy is so prevalent. In this study, the team discovered that this deletion on chromosome 8 is more likely to involve the oncogene WRN than other regions, suggesting its particularly significant impact.
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. This observation could pave the way for new cancer treatments—approaches to selectively eliminating cancer cells containing the missing WRN—and also aid in identifying patients most likely to benefit from these treatments.
The team emphasized that many of the regions identified in the study could serve as new drug targets or aid in screening cancer patients to determine the most effective treatments.