Researchers at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center have uncovered pivotal evidence linking extra copies of chromosome segment 1q to the early development of pancreatic cancer. This discovery, published on February 20 in Science Advances, could reshape our understanding of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer.
After analyzing genetic data from over 800 pancreatic tumors and precancerous lesions, the research team identified chromosome 1q gains as one of the most frequent chromosomal changes in PDAC. These gains often occur before other well-known genetic alterations that drive cancer.
Unveiling Chromosomal Changes
The study, supported by the National Institutes of Health, involved whole-genome sequencing of 535 pancreatic cancers. Researchers confirmed that chromosome 1q gains were present in nearly 40% of cases, marking it as the second most frequent chromosomal gain in PDAC. The use of fluorescence in situ hybridization (FISH) further revealed that many tumors contained extra copies of chromosome 1q, even when sequencing methods failed to detect the abnormality initially.
“For years, the field has focused primarily on mutations, but that approach has left a gap in our understanding,” stated Christopher Douville, Ph.D., assistant professor of oncology and first author of the study. “We suspected that part of the missing genetic story might lie in much larger chromosomal changes that affect hundreds or even thousands of genes at once.”
Pinpointing Genetic Drivers
To uncover these missing drivers, the team assembled a large and diverse dataset, including invasive cancers and various precancerous lesions. This extensive data allowed them to narrow down which parts of the chromosome were consistently altered in lesions that progress to cancer.
By examining tumors with partial chromosome 1q duplication, researchers pinpointed two small regions that were consistently gained. These regions contain genes such as NCSTN and PSEN2, which encode components of the γ-secretase complex, a critical player in cell behavior regulation. Further analysis showed that the expression of these genes correlated with chromosome 1q gains, identifying them as potential oncogene drivers in early pancreatic cancer.
Implications for Early Detection and Treatment
To understand the timing of these changes, the team extended their analysis to 267 precancerous pancreatic lesions. They discovered that chromosome 1q gains were rare in low-grade lesions but common in high-grade ones, which are more likely to progress to invasive cancer. This suggests that chromosome 1q duplication may represent an early step in pancreatic tumor evolution.
“Chromosome 1q gains were the most common chromosomal alteration observed across the earliest stages of pancreatic tumor development, often preceding other genetic changes known to be involved in PDAC,” Douville explained.
These findings suggest that duplication of γ-secretase genes may provide a selective growth advantage during pancreatic cancer initiation and progression.
While further functional studies are needed to confirm the biological mechanisms, this discovery could lead to new targeted therapies or improved diagnostic tools for early detection of pancreatic cancer. The researchers also plan to explore whether similar chromosome 1q gains are present in other cancer types.
Research Team and Funding
The study involved a collaborative effort among researchers including Laura Wood, M.D., Ph.D., Jeeun Parksong, Marco Dal Molin, and many others. It was funded by various grants from the National Institutes of Health, the Lustgarten Foundation, and several other foundations and endowments.
However, the study’s authors disclosed several competing interests, including equity holdings and consultancies with companies like Thrive Earlier Detection, Exact Sciences, and Haystack Oncology. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
As the scientific community delves deeper into the genetic underpinnings of pancreatic cancer, the findings from Johns Hopkins offer a promising new avenue for research and potential clinical applications. The next steps involve functional studies to test how these genetic changes contribute to cancer development, with the hope of paving the way for innovative treatments and early detection strategies.
