Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Abstract

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

“…For PDAC in general, high-TMB PDAC mainly involve the pancreatic head, with more than 60% of cases resulting in this location. In terms of histologic subtypes, there is a higher prevalence of mucinous-colloid and medullary histology, which usually represent less than 2% of all PDAC [47][48][49][50] but, in the case of high-TMB, PDAC represent 14% and 4% of all cases, respectively. These differences are statistically significant and, at least in part, reflect the association of high-TMB with MSI/dMMR in PDAC, where these histological variants have already been demonstrated to be more prevalent [35,[51][52][53].…”

Molecular alterations in pancreatic tumors

“…Even if uncommon, MSI/dMMR (Microsatellite Instability/defective DNA mismatch repair) has been described in about 1%-2% of PDAC[ 62 , 63 ]. PDACs with MSI are usually associated with medullary histology and are rarely mutated in KRAS or TP53 genes[ 62 , 64 ]. National Comprehensive Cancer Network (NCCN) guidelines recommend the MSI and MMR tests in locally advanced and metastatic pancreatic carcinomas[ 65 ].…”

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

“…In the case of missense mutations of GNAS gene, such as those resulting in R201H and R201C variants, the encoded protein is constitutionally active. Among gastrointestinal tract neoplasms, such GNAS gene alterations have been found in pancreatic intraductal papillary mucinous neoplasms (mostly of intestinal type) and colloid carcinomas [ 31 , 32 , 33 ], low-grade appendiceal mucinous neoplasms/pseudomyxoma peritonei [ 30 ], intestinal villous adenomas [ 34 ], in addition to gastric and duodenal pyloric gland adenomas and duodenal adenocarcinoma [ 16 , 21 , 27 , 35 ]. Interestingly, in duodenal adenocarcinoma, GNAS mutation was associated with gastric phenotype [ 35 ], suggesting that pyloric gland adenomas might represent the precursor lesions of duodenal adenocarcinomas with gastric differentiation.…”