Genomic determinants of biological aggressiveness and poor prognosis of pancreatic cancers: KRAS and beyond

ABSTRACT

Introduction

A marked histomolecular heterogeneity characterizes pancreatic cancer. Thus, different tumor histologies with divergent genomic profiles exist within the same category.

Areas covered

Using data from PubMed, SCOPUS, and Embase (last search date: 04/04/2024), this expert-based, narrative review presents and discusses the essential molecular determinants of biological aggressiveness and poor prognosis in pancreatic cancer. First, KRAS mutation still represents one of the most critical difficulties in treating pancreatic cancers. In this district, it is mutated in > 90% of malignant tumors. Notably, actionable alterations for molecular-based therapies are typically lacking in KRAS-mutated pancreatic cancer. Furthermore, transcriptome-based studies clarified that the squamous phenotype is characterized by poorer prognosis and response to standard chemotherapy. We also discuss molecular biomarkers related to dismal prognosis in specific subsets of pancreatic cancer, such as SMAD4 in signet-ring cell carcinoma and TP53 in invasive cancers derived from intraductal tubulopapillary neoplasms.

Expert opinion

The identification of the subgroups of pancreatic cancer with particularly unfavorable prognoses is a critical step for addressing specific research efforts. In addition to implementing and strengthening current precision oncology strategies, the decisive step for improving the survival of patients affected by pancreatic cancer must pass through targeting the KRAS gene.

KEYWORDS:

• KRAS
• pancreatic cancer
• pancreatic ductal adenocarcinoma
• SMAD4
• TP53
• transcriptome

Article highlights

• Pancreatic cancer is one of the most lethal solid malignancies.

• The molecular determinants of biological aggressiveness and poor prognosis are discussed.

• KRAS mutations and the squamous phenotype are the two molecular hallmarks of poor prognosis.

• SMAD4 is a marker of poor prognosis in signet-ring cell carcinoma.

• TP53 is a marker of poor prognosis in invasive cancers derived from ITPN.

• The decisive step for improving the survival of patients must pass through targeting KRAS.

Declaration of interest

C. Luchini has the following conflict of interest: he received honoraria for expert consultancy from NTP, and honoraria for lectures from MSD and Medica s.r.l. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers in this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study is supported by Italian Ministry of University and Research, through a “Project of significant national interest” (PRIN 2022, code: 2022CMMRWA, CUP: B53D23008010006) to C.L.