Researchers at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center uncovered new evidence that extra copies of a specific chromosome segment - chromosome 1q - may play a key role in the earliest stages of pancreatic cancer development. After analyzing genetic data from more than 800 pancreatic tumors and precancerous lesions, the team found that gains of chromosome 1q are among the most frequent chromosomal changes in pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, and often arise before other well-known cancer-driving genetic alterations.
A report of the study was published Feb. 20 in Science Advances. The research was supported, in part, by the National Institutes of Health.
The research team examined whole-genome sequencing data from 535 pancreatic cancers, reading all of the DNA from the tumors, and confirmed that chromosome 1q gains were present in nearly 40% of cases, making it the second most frequent chromosomal gain observed in PDAC. With fluorescence in situ hybridization (FISH), which uses glowing tags to highlight genetic changes inside cells, the researchers showed that many tumors contained extra copies of chromosome 1q in the majority of cancer cells - even in cases where sequencing methods did not initially detect the abnormality - suggesting that these gains may be more widespread than previously appreciated.
"For years, the field has focused primarily on mutations, but that approach has left a gap in our understanding," says 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."
To uncover those missing drivers, Douville and colleagues assembled an unusually large and diverse dataset, including invasive cancers and multiple types of precancerous lesions.
"That scale gave us the resolution we needed to narrow down which parts of the chromosome were consistently altered in lesions that go on to become cancer," Douville says.
By closely examining tumors in which only part of chromosome 1q was duplicated, the researchers were able to pinpoint two small regions that were repeatedly gained. Both regions contain genes, including NCSTN and PSEN2, that encode subunits of the γ-secretase complex, which functions like molecular scissors, cutting and processing other proteins inside cells that regulate cell behavior. Further analysis showed that expression of these genes correlated with the presence of chromosome 1q gains, identifying them as strong candidate oncogene drivers (genes that support tumor growth) in early pancreatic cancer.
"Based on the genetic evidence, these genes rise to the top as the most likely drivers within the duplicated regions," says Laura Wood, M.D., Ph.D., associate professor of pathology and co-leader of the study. "The next step is functional work to test exactly how they contribute to cancer development."
To understand when these changes occur, the team extended their analysis to 267 precancerous pancreatic lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs). They found that chromosome 1q gains were rare in low-grade PanINs but common in high-grade PanINs and IPMNs, lesions thought to carry a higher risk of progressing to invasive cancer. In many of these high-grade precursor lesions, chromosome 1q gains appeared in the absence of additional chromosomal abnormalities or mutations in classic pancreatic cancer driver genes, indicating that the duplication of chromosome 1q 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, and often preceded alterations in other genes known to be involved in PDAC," says Douville.
The findings, which provide a clearer picture of the earliest steps of pancreatic cancer development, suggest that duplication of γ-secretase genes may provide a selective growth advantage during pancreatic cancer initiation and progression. Although the researchers note that additional functional studies will be needed to confirm the biological mechanisms underlying these effects, they say it could be the impetus for a new targeted therapy, using a drug to block or inhibit genes, or to improve pancreatic cancer diagnostics and early detection. The researchers also plan to explore whether similar chromosome 1q gains play a role in other cancer types.
In addition to Douville and Wood, other researchers participating in the study were Jeeun Parksong, Marco Dal Molin, Sarah Graham, Patricia Greipp, Ryan Knudson, Samuel Curtis, Yuxuan Wang, Lisa Dobbyn, Maria Popoli, Janine Ptak, Natalie Silliman, Katharine Romans, Christine Icobuzio-Donahue, Alvin Makoohon-Moore, Anne Marie Lennon, Michael Goggins, Ralph Hruban, Ashley Kieman, Chetan Bettegowda, Kenneth Kinzler, Nickolas Papadopoulos and Bert Vogelstein.
This study was supported by National Institutes of Health grants RA37CA230400, U01CA230691, U54 CA274371, U01CA210170, Oncology Core CA 06973, 5P50CA062924-22, and R00CA229979, Lustgarten Foundation, Virginia and D.K. Ludwig Fund for Cancer Research, Commonwealth Fund, Sol Goldman Pancreatic Cancer Research Center and Sequencing Facility at Johns Hopkins, Benjamin Baker Endowment 80049589, JHTV Innovation Grant, Florence D. and Irving J. Sherman MD Charitable Foundation Trust, New Jersey Health Foundation, Scott R. MacKenzie Foundation, and Rolfe Pancreatic Cancer Foundation.
The investigators report the following competing interests: Vogelstein, Kinzler and Papadopoulos are founders of Thrive Earlier Detection, an Exact Sciences Company. Kinzler, Papadopoulos and Douville are consultants to Thrive Earlier Detection and hold equity in Exact Sciences. Papadopoulos and Douville are consultants to Thrive Earlier Detection. Vogelstein, Kinzler and Papadopoulos are founders of and own equity in Haystack Oncology, a Quest company, and ManaT Bio. Kinzler and Papadopoulos are consultants to Neophore. Kinzler, Vogelstein and Papadopoulos hold equity in and are consultants to CAGE Pharma. Vogelstein is a consultant to and holds equity in Catalio Capital Management. Bettegowda is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology and Galectin Therapeutics and is a co-founder of OrisDx. Bettegowda and Douville are co-founders of Belay Diagnostics. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from The Johns Hopkins University. Vogelstein, Kinzler, Papadopoulos, Bettegowda and Douville are inventors of some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to The Johns Hopkins University. Patent applications on the work described in this paper may be filed by The Johns Hopkins University. The terms of all these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. All other authors declare that they have no competing interests.
