Clinicogenomic Landscape of Pancreatic Ductal Adenocarcinoma: The Prognostic Role of KRAS Mutation Dosage

Academic Background

Pancreatic ductal adenocarcinoma (PDAC), the most common histological type of pancreatic cancer, is the third leading cause of cancer-related mortality and has the lowest five-year survival rate among all cancer types. Over 90% of PDAC patients carry hotspot mutations in the KRAS gene, which have long eluded targeted therapeutic approaches. Although recent advances have been made in targeting KRAS mutations, the role of genomic biomarkers in predicting disease outcomes remains unclear. In particular, the relationship between increased KRAS mutation dosage and disease progression has not been thoroughly studied. Therefore, this study aims to reveal the prognostic significance of KRAS mutation dosage in PDAC through large-scale clinicogenomic data analysis, providing new insights for clinical practice.

Led by a research team from Memorial Sloan Kettering Cancer Center (MSK), the study was published in Nature Medicine in February 2025. By performing genomic sequencing on tumor and normal tissues from 2,336 PDAC patients and combining detailed clinical follow-up data, the research systematically analyzed the relationship between KRAS mutation dosage and patient prognosis. The results showed that an increase in KRAS mutation dosage is a hallmark of PDAC disease progression and has prognostic significance across all stages of the disease.

Research Workflow

1. Construction of the Study Cohort

The study included 2,336 PDAC patients treated at MSK between January 2014 and September 2021. Tumor and normal tissues from all patients were molecularly tested using MSK-IMPACT, an FDA-authorized clinical sequencing panel. The MSK-IMPACT panel covers up to 505 cancer genes, with a median sequencing depth of 606×. Samples with low sequencing coverage (<100×) or no detectable somatic mutations were excluded, leaving representative samples from 2,336 patients for final inclusion.

2. Genomic Feature Analysis

The research team first conducted a comprehensive analysis of the genomic characteristics of PDAC tumors. The results showed that 95% of tumors carried KRAS mutations, with the most common mutation sites being G12 (91%) and Q61 (7%). Additionally, in KRAS wild-type (KRASwt) tumors, about 60% carried mutations in other MAPK pathway genes such as BRAF, NRAS, NF1, etc. The study also found that KRASwt tumors could be divided into two categories: those carrying mutations in other MAPK pathway genes (Other-MAPKmut) and those without any MAPK pathway mutations (MAPKwt). These two types of tumors exhibited significant differences in age of onset, genomic features, and prognosis.

3. Relationship Between KRAS Mutation Dosage and Prognosis

The research team further analyzed the relationship between increased KRAS mutation dosage and patient prognosis. Through allele-specific copy number analysis of 1,157 KRAS-mutated tumors, it was found that 42% of tumors exhibited allelic imbalance at the KRAS locus, with 19% having undergone whole-genome doubling (WGD). Increased KRAS mutation dosage was closely associated with disease progression, especially more common in metastatic tumors. The study results indicated that increased KRAS mutation dosage is a significant marker of poor prognosis in PDAC patients.

4. Assessment of Clinical Actionability

The study also evaluated the clinical actionability of PDAC patients. About 10% of patients harbored standard-of-care biomarkers, such as high microsatellite instability (MSI-H) or MAPK pathway gene mutations. Additionally, 78% of patients carried biomarkers with clinical evidence, the vast majority (98%) of which were KRAS G12D/V/R/A/S mutations. These findings provide important bases for future targeted therapies.

Main Results

1. Increased KRAS Mutation Dosage Associated with Disease Progression

The study found that increased KRAS mutation dosage was closely related to PDAC disease progression. In non-WGD tumors, patients with increased KRAS mutation dosage had significantly shorter overall survival (HR=1.7, p=3.5×10^-7). This finding was validated across different disease stages, indicating that increased KRAS mutation dosage is a significant marker of poor prognosis in PDAC.

2. Molecular Subtypes of KRASwt Tumors

The study found that KRASwt tumors could be divided into Other-MAPKmut and MAPKwt types. Other-MAPKmut tumors carried mutations in other MAPK pathway genes, while MAPKwt tumors did not carry any MAPK pathway mutations. These two types of tumors exhibited significant differences in age of onset, genomic features, and prognosis. Notably, patients with MAPKwt tumors had an earlier age of onset (median age 58 years) and carried more germline mutations in the ATM gene.

3. Assessment of Clinical Actionability

The study assessed the clinical actionability of PDAC patients and found that about 10% of patients harbored standard-of-care biomarkers, such as MSI-H or MAPK pathway gene mutations. Additionally, 78% of patients carried biomarkers with clinical evidence, the vast majority (98%) of which were KRAS G12D/V/R/A/S mutations. These findings provide important bases for future targeted therapies.

Conclusion and Significance

Through the analysis of clinicogenomic data from 2,336 PDAC patients, this study revealed the prognostic significance of KRAS mutation dosage in PDAC. The results showed that increased KRAS mutation dosage is a hallmark of PDAC disease progression and has prognostic significance across all disease stages. Additionally, the study found that KRASwt tumors can be divided into two categories with different molecular features and clinical outcomes. These findings provide new insights for precision treatment of PDAC, especially with important clinical implications in the field of KRAS-targeted therapy.

Highlights of the Study

1. Prognostic Significance of KRAS Mutation Dosage: The first large-scale study to reveal the relationship between increased KRAS mutation dosage and poor prognosis in PDAC patients.
2. Molecular Subtypes of KRASwt Tumors: Discovered two molecular subtypes of KRASwt tumors, providing new bases for precise classification of PDAC.
3. Assessment of Clinical Actionability: Evaluated the clinical actionability of PDAC patients, providing important bases for future targeted therapies.

Other Valuable Information

The research team also developed a new algorithm for allele-specific copy number analysis, improving the sensitivity and specificity of KRAS mutation dosage detection. This algorithm is expected to be applied in genomic analysis of other cancer types in the future.

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This study provides important scientific evidence for precision treatment of PDAC, especially with significant clinical implications in the field of KRAS-targeted therapy. Future research can further explore the role of KRAS mutation dosage in targeted therapy and how to apply these findings in clinical practice.