Pancreatic cancer (PC) is a recalcitrant and serious disease caused by abnormal cell division and uncontrolled growth in the pancreas. The mortality rate of PC is rapidly increasing and PC is expected to be the second most common of all malignant tumors by 2030.
Key features of PC
- PC is a malignant tumor with an extremely complex genomic landscape and characterized by high incidence and poor prognosis.
- The 5-year relative survival rate for PC patients worldwide has been reported to be 2%~ 9%.
- More than 85% of PC cases are Pancreatic Ductal Adenocarcinoma (PDAC), an exocrine malignancy.
- With few breakthroughs in practice over the past 30 years, there is a growing need to develop new and improved treatment strategies.
- New therapeutic options are highly desirable, for example from a genomic and transcriptomic subtype perspective, and require additional preclinical and clinical evaluation.
Common symptoms in PDAC patients include nausea, dyspnea, bloating/abdominal distention, constipation, anxiety and depression. As a result, the disease can lead to weight loss and malnutrition in patients. In addition, abdominal pain and back pain are among the most common symptoms of the disease.
Fig1. Common signs and symptoms by site of pancreatic tumour. (Mizrahi, J. D.,et al., 2020)
|Risk factors for developing PC|
|Non-modifiable risk factors (Specific description)||Modifiable risk factors (Direction of association)|
|Age (Mostly seen in the elderly, aged >55)||Smoking (Positive)|
|Sex (The incidence is higher in men than in women)||Alcohol (Mixed between no association and positive)|
|Ethnicity (Differences in incidence were observed between ethnic groups)||Chronic pancreatitis (Positive)|
|Blood group (Compared to blood patients with blood group O, patients with blood group A, AB, or B were at a significantly higher risk of developing PC)||Obesity (Positive)|
|Gut Microbiota (The gut microbiota reportedly involved in PC risk)||Dietary factors (Variable)|
|Family history and genetic susceptibility (PC shows a strong genetic susceptibility)||Infection (such as Helicobacter pylori (H-pylori) and hepatitis C infections, Positive)|
|Diabetes (a well-established risk factor for PC)|
Pathology and molecular understanding of PDAC pathogenesis
PDAC has three best-characterized precursors that have unique clinical, pathological, and molecular features, including intraductal papillary mucinous neoplasms (IPMN), pancreatic intraepithelial neoplasia (PanIN), and mucinous cystic neoplasms (MCN). Approximately 60-70% of PC occur in the head of the pancreas, with the remainder arising in the body (15%) and tail (15%) of the pancreas. It is common for most PDAC to have spread beyond the pancreas by the time of diagnosis. PDAC is complex and heterogenous and can be further explained by its molecular signatures.
There are many high-frequency gene mutations in PC, such as KRAS, CDKN2A, TP53, RNF43, SMAD4, etc., and other potentially druggable mutations with a lower prevalence can be revealed using combined analysis. According to recent genomic analysis studies, the recurrently mutated genes in PC can be divided into four sub-groups, including pancreatic progenitor, squamous, immunogenic, and aberrantly differentiated endocrine exocrine. These sub-types have unique genomic signatures that correspond to histopathological findings and prognosis.
-The pancreatic progenitor group: High expression of transcription factors involved in determining the pancreatic cell lineage.
-The squamous group: Associated with the adenosquamous histological variant of PDAC and was found to have an independent poor prognosis.
-The immunogenic sub-type: Discovery of immunogenic tumors with significant immune infiltration.
-The aberrantly differentiated endocrine exocrine group: Associated with acinar cell carcinomas.
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