According to the American Cancer Society (ACS), pancreatic ductal adenocarcinoma (PDAC) will affect approximately 67,440 Americans in 2026, with a 5-year survival rate of just 13%. The disease accounts for about 3% of all cancers in the United States and about 8% of all cancer deaths. [1]
PDAC develops within the pancreatic ductal system and is typically driven by somatic activation of the oncogene KRAS, with mutations present in over 90–95% of pancreatic ductal adenocarcinomas (Particularly the KRASG12C oncoprotein, which causes the KRAS protein to remain constantly ‘on,’ driving uncontrolled cancer cell growth, metabolism, and therapeutic resistance), along with the inactivation of two or three tumor suppressor genes—CDKN2A, TP53, and SMAD4. [2][3][4]
Early-stage cancer
Now, scientists 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 researchers 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, which, in part, was supported by the National Institutes of Health (NIH), Oncology Core CA, the Lustgarten Foundation, Virginia, and D.K. Ludwig Fund for Cancer Research, and other governmental and philanthropic organisations, was published on February 20, 2026, in Science Advances.[5]
Chromosomal gain
The team examined whole-genome sequencing data from 535 pancreatic cancers, analyzing all tumor DNA, and confirmed that chromosome 1q gains were present in 213 (39.8%) of PDAC cases, making it the second-most-frequent chromosomal gain in pancreatic ductal adenocarcinoma.
With fluorescence in situ hybridization (FISH), which uses glowing tags to highlight genetic changes inside cells, the researchers demonstrated 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.
Christopher B. Douville, Ph.D, Assistant Professor of Oncology, Johns Hopkins School of Medicine Faculty. Photo courtesy © 2024 – 2026 The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System. Used with permission.“For years, the field has focused primarily on mutations, but that approach has left a gap in our understanding,” says Christopher B. 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 pinpointed 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.
The authors found that 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.
Laura Delong Wood, MD, Ph.D.,Professor of Pathology, Photo courtesy © 2024 – 2026 The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System. Used with permission.
“Based on the genetic evidence, these genes rise to the top as the most likely drivers within the duplicated regions,” explained 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,” she added.
Precancerous pancreatic lesions
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 occurred in the absence of additional chromosomal abnormalities or mutations in classic pancreatic cancer driver genes, suggesting that 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, and often preceded alterations in other genes known to be involved in PDAC,” Douville said.
A clearer picture
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 are associated with other cancer types.
Reference
[1] Key Statistics for Pancreatic Cancer. American Cancer Society (ACS) Online. Last accessed in February 2026.
[2] Luo J. KRAS mutation in pancreatic cancer. Semin Oncol. 2021 Feb;48(1):10-18. doi: 10.1053/j.seminoncol.2021.02.003. Epub 2021 Feb 23. PMID: 33676749; PMCID: PMC8380752.
[3] Stefanoudakis D, Frountzas M, Schizas D, Michalopoulos NV, Drakaki A, Toutouzas KG. Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer. Curr Issues Mol Biol. 2024 Mar 23;46(4):2827-2844. doi: 10.3390/cimb46040177. PMID: 38666907; PMCID: PMC11049225.
[4] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013 Mar 29;339(6127):1546-58. doi: 10.1126/science.1235122. PMID: 23539594; PMCID: PMC3749880.
[5] Douville C, Parksong J, Molin MD, Graham S, Greipp PT, Knudson R, Curtis S, Wang Y, Dobbyn L, Popoli M, Ptak J, Silliman N, Romans K, Iacobuzio-Donahue CA, Makoohon-Moore AP, Lennon AM, Goggins M, Hruban RH, Kiemen A, Bettegowda C, Kinzler KW, Papadopoulos N, Wood LD, Vogelstein B. Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia.Sci. Adv.12,eadx7501(2026).DOI:10.1126/sciadv.adx7501
Featured Image: Cancerous cells forming a lump in the pancreatic tissue. Photo courtesy: Scientific Animations. Licensed under the Creative Commons Attribution-Share Alike 4.0 International license.
DOI
){kind=link}