Histological and Molecular Aspects of Pancreatic Carcinogenesis Flashcards
What is the debate regarding the origin of PDAC?
The question of whether there is a single cell of origin for the development of PDAC is still a matter of debate.
How does PDAC develop?
PDAC develops through acinar-ductal metaplasia (ADM) and several neoplastic precursor lesions in a stepwise process.
What are the three different precursor lesions of PDAC?
The three different precursor lesions are pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), and mucinous cystic neoplasms (MCN).
Which precursor lesions are the most frequent in PDAC?
Pancreatic intraepithelial neoplasia (PanIN) lesions are the most frequent precursor lesions of PDAC.
How are PanIN lesions detected?
PanIN lesions can only be detected microscopically and not by clinical imaging modalities.
How are PanIN lesions graded?
PanIN lesions can be graded from PanIN 1 to PanIN 3 based on histopathological appearance from low- to high-grade dysplasia.
What characterizes high-grade PanIN-3 lesions?
High-grade PanIN-3 lesions reveal severe nuclear atypia, luminal necrosis, and epithelial cell budding into the ductal lumen.
Do all PanIN lesions progress to PDAC?
PanIN-1 and PanIN-2 lesions may not necessarily progress to PanIN-3 and PDAC and can often be found in older people and in pancreatitis patients.
What accompanies morphological alterations during PanIN-PDAC progression?
Morphological alterations are accompanied by key mutations in oncogenes and tumor suppressor genes.
What mutation occurs early during PDAC tumorigenesis?
Activating KRAS mutations occur early during tumorigenesis and are present in almost 100% of all PDAC patients.
Which tumor suppressor gene is often inactivated during early carcinogenesis?
The tumor suppressor gene CDKN2A (encoding for p16 and p14Arf) is often found to be inactivated during early carcinogenesis.
What is the frequency of TP53 mutations in PanIN-3 lesions?
Inactivating mutations of the TP53 (p53) tumor suppressor gene occur at high frequencies in PanIN-3 lesions and frank carcinomas.
Which additional tumor suppressor genes are mutated at lower frequencies?
Additional tumor suppressor genes that are mutated at lower frequencies include DPC4/SMAD4 and BRCA2.
What recent findings reveal about the origin of PDAC?
Recent work has revealed that both acinar and ductal cells can give rise to PDAC using GEMMs with directed key mutations.
What was observed regarding tumor latency in acinar vs ductal cells?
KRAS and TP53 mutations induced in acinar cells revealed a longer latency until invasive PDAC was initiated compared to ductal cells.
What does the study highlight about disease progression?
The study highlights the importance of the cellular context for disease progression and tumor type.
