Johns Hopkins Researchers Uncover Early Driver in Pancreatic Cancer Development

Researchers at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center have discovered new evidence suggesting that extra copies of a specific chromosome segment, chromosome 1q, may be critical in the earliest stages of pancreatic cancer development.

Analysis of genetic data from over 800 pancreatic tumors and precancerous lesions revealed that gains of chromosome 1q are among the most frequent chromosomal changes in pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. These gains often emerge before other known cancer-driving genetic alterations.

Whole-genome sequencing data from 535 pancreatic cancers indicated chromosome 1q gains in nearly 40% of cases, making it the second most frequent chromosomal gain in PDAC. Further investigation using fluorescence in situ hybridization (FISH) suggested these gains might be even more widespread than initially detected.

Identified Driver Genes

By examining tumors where only parts of chromosome 1q were duplicated, the team pinpointed two small regions consistently gained. Both regions contain genes, including NCSTN and PSEN2, which encode subunits of the γ-secretase complex. This complex processes proteins regulating cell behavior. The expression of these genes correlated with the presence of chromosome 1q gains, identifying them as strong candidate oncogene drivers in early pancreatic cancer.

Timing of Alterations

The analysis was extended to 267 precancerous pancreatic lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs). Chromosome 1q gains were found to be rare in low-grade PanINs but common in high-grade PanINs and IPMNs, which carry a higher risk of progressing to invasive cancer. In many high-grade precursor lesions, chromosome 1q gains appeared independently of other chromosomal abnormalities or mutations in classic pancreatic cancer driver genes, suggesting this duplication is an early step in pancreatic tumor evolution.

Implications for Treatment and Detection

These findings provide a clearer understanding of the initial stages of pancreatic cancer, indicating that duplication of γ-secretase genes might offer a selective growth advantage during cancer initiation and progression. This discovery could lead to new targeted therapies, improved diagnostics, and earlier detection methods for pancreatic cancer. Further functional studies are planned to confirm the biological mechanisms. The researchers also intend to explore similar chromosome 1q gains in other cancer types.

Funding and Disclosures

The study received support from various grants, including those from the National Institutes of Health, the Lustgarten Foundation, and the Ludwig Fund for Cancer Research. Several investigators reported competing interests related to companies that have licensed technologies from Johns Hopkins University.