Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.
The target lesions for pancreatic cancer screening are high-grade precancerous lesions and early-stage invasive cancers.
Precancerous lesions can be microscopic (pancreatic intraepithelial neoplasia (PanIN)) or macroscopic (intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN)), and these lesions are classified as low-grade or high-grade based on the morphological grade of dysplasia of their lining epithelium; although low-grade lesions share early oncogene mutations such as KRAS, mutations in other genes (CDKN2A, TP53 and SMAD4) are limited to more advanced lesions.
Studies have highlighted genetic heterogeneity in precancerous lesions and multifocal neoplasia in the pancreas, which should be considered when designing early detection approaches.
The evolving understanding of the genetics of precancerous lesions has led to the development of clinically available assays for pancreatic cyst classification and detection of high-grade dysplasia and early-stage pancreatic cancers.
Mutations in KRAS and/or GNAS are highly specific for mucinous cysts, such as IPMNs, while alterations in CDKN2A, TP53 and/or SMAD4 are almost exclusively seen in the setting of advanced lesions.
The assessment of genetic alterations using a non-invasive method, such as from a patient’s blood specimen, holds promise not only for early detection of pancreatic cancer but also for the identification of precancerous lesions.
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The authors declare no competing interests.
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Singhi, A.D., Wood, L.D. Early detection of pancreatic cancer using DNA-based molecular approaches. Nat Rev Gastroenterol Hepatol 18, 457–468 (2021). https://doi.org/10.1038/s41575-021-00470-0