Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer

Round 1

Reviewer 1 Report

The review discussed the significance of four genes—TP53, CDKN2A, SMAD4, and KRAS—in pancreatic cancer with the following key points: These four genes play crucial roles in tumor suppression or progression and are frequently mutated in pancreatic cancer, affecting tumor development and progression. Specific mutations, like the loss of TP53, have significant prognostic implications, influencing survival rates and treatment responses. It explored potential targeted therapies tailored to these molecular signatures, highlighting the importance of genomic analyses for personalized treatment. This comprehensive analysis aims to pave the way for more effective therapeutic interventions by understanding the molecular intricacies of pancreatic cancer. Therefore, this is a useful and interesting review. Only one suggestion is that it should be provided a separate table listing nonclinical and clinical studies targeting each factor.

Minor language polishing will be required.

Author Response

Answers to reviewer 1

The review discussed the significance of four genes—TP53, CDKN2A, SMAD4, and KRAS—in pancreatic cancer with the following key points: These four genes play crucial roles in tumor suppression or progression and are frequently mutated in pancreatic cancer, affecting tumor development and progression. Specific mutations, like the loss of TP53, have significant prognostic implications, influencing survival rates and treatment responses. It explored potential targeted therapies tailored to these molecular signatures, highlighting the importance of genomic analyses for personalized treatment. This comprehensive analysis aims to pave the way for more effective therapeutic interventions by understanding the molecular intricacies of pancreatic cancer. Therefore, this is a useful and interesting review.

Authors’ reply

Thank you very much for your insightful comment! I'm glad you found the review useful and interesting. Your feedback is greatly appreciated!  It's indeed fascinating to delve into the molecular intricacies of pancreatic cancer and explore potential targeted therapies based on specific genetic mutations.

Only one suggestion is that it should be provided a separate table listing nonclinical and clinical studies targeting each factor.

Authors’ reply

Thank you for the suggestion. Acknowledging the importance of providing separate tables for nonclinical and clinical studies targeting each factor, I have made the necessary adjustments to incorporate this feedback. As another reviewer also suggested a similar modification, we have updated Table 1 accordingly. Thank you for your input!

Minor language polishing will be required.

Authors’ reply

Thank you! We have revised the paper and we edited the spelling mistakes.

Reviewer 2 Report

The review by Stefanoudakis et al. examines key tumor suppressor genes, such as TP53, CDKN2A, and SMAD4, associated with pancreatic cancer. It explores the role, prevalence, and impact of each gene on tumor development, highlighting the intricate molecular landscape of the disease. Additionally, the review discusses the prognostic significance of specific mutations, such as TP53 loss, and investigates potential targeted therapies based on these molecular signatures. It emphasizes the importance of genomic analyses for risk assessment, early detection, and personalized treatment planning in pancreatic cancer. Overall, the review provides a comprehensive analysis of the molecular complexities of pancreatic tumors, laying the foundation for more effective and personalized therapeutic approaches.

·       I find the topic authentic and relevant, addressing a specific gap in the field. This review promises to provide valuable insights into the understanding of pancreatic cancer's molecular mechanisms and its implications for personalized treatment strategies.

·       The methodology is fine and no further control is required.

·       I found the conclusion to be in line with the evidence and arguments presented.

·       The references are well-updated.

The manuscript is interesting, however, it can be improved and strengthened by addressing the following comments –

·       It is advisable that authors utilize more recent references, preferably within the past 5-6 years, to ensure the incorporation of the latest advancements and findings in the field.

·       The captions for Figures 2 and 3 require clarification.

·       In Table 1, TP53 regulates the cell cycle, DNA repair, and apoptosis, with references [7,8]. However, it's important to note that reference 7 is a review article, while reference 8 is a research article, which may lead to confusion. Additionally, TP53 plays a diverse role in cell cycle arrest, DNA repair, apoptosis, autophagy (PMID: 32987354), and ferroptosis (PMID: 35685623). However, in pancreatic cancer, TP53 is commonly mutated. Considering this, it may be prudent to reassess whether including TP53 in Table 1 is appropriate.

 Minor editing of the English language is required.

Author Response

Answers to reviewer 2

The review by Stefanoudakis et al. examines key tumor suppressor genes, such as TP53, CDKN2A, and SMAD4, associated with pancreatic cancer. It explores the role, prevalence, and impact of each gene on tumor development, highlighting the intricate molecular landscape of the disease. Additionally, the review discusses the prognostic significance of specific mutations, such as TP53 loss, and investigates potential targeted therapies based on these molecular signatures. It emphasizes the importance of genomic analyses for risk assessment, early detection, and personalized treatment planning in pancreatic cancer. Overall, the review provides a comprehensive analysis of the molecular complexities of pancreatic tumors, laying the foundation for more effective and personalized therapeutic approaches.

• I find the topic authentic and relevant, addressing a specific gap in the field. This review promises to provide valuable insights into the understanding of pancreatic cancer's molecular mechanisms and its implications for personalized treatment strategies.
• The methodology is fine and no further control is required.
• I found the conclusion to be in line with the evidence and arguments presented.
• The references are well-updated.

Authors’ reply

Thank you for your comment. Thank you so much for your detailed and positive feedback on our review!  

The manuscript is interesting, however, it can be improved and strengthened by addressing the following comments –

• It is advisable that authors utilize more recent references, preferably within the past 5-6 years, to ensure the incorporation of the latest advancements and findings in the field.

Authors’ reply

 Thank you very much for the comment and we totally agree with your point. As you already noticed the majority of articles used as bibliography are published in the last 1-6 years. Nevertheless, we also used some classic articles from earlier years which we thought to help to give a time-to-time highlighting of the importance of studying the role of TP53, CDKN2A, SMAD4 and KRAS in pancreatic cancer.

• The captions for Figures 2 and 3 require clarification.

Authors’ reply

Thank you for your comment. Regarding figure 2 the following clarification has been added: “TGF-β binds to cytoplasmic membrane receptors, triggering downstream signaling cascades. One key pathway involves the formation of a SMAD4–SMAD2/3 complex, which translocates into the nucleus and regulates the expression of target genes, influencing various cellular processes. This mechanism illustrates how TGF-β signaling via SMAD proteins modulates gene expression and cellular responses.”. Moreover, for figure 3 the following part has been added according to your suggestion: “The KRAS pathway, including PI3K, RAF, and RAL, operates synergistically to regulate key cellular processes such as proliferation, survival, and metabolism. Upon activation by extracellular signals, KRAS initiates a signaling cascade that involves the activation of PI3K, RAF, and RAL proteins. These downstream effectors act in concert to propagate signaling, leading to the activation of various pathways involved in cell growth and survival. Dysregulation of this synergistic network, often through mutations in KRAS or its effectors, contributes to cancer development and progression.”.

     In Table 1, TP53 regulates the cell cycle, DNA repair, and apoptosis, with references [7,8]. However, it's important to note that reference 7 is a review article, while reference 8 is a research article, which may lead to confusion. Additionally, TP53 plays a diverse role in cell cycle arrest, DNA repair, apoptosis, autophagy (PMID: 32987354), and ferroptosis (PMID: 35685623). However, in pancreatic cancer, TP53 is commonly mutated. Considering this, it may be prudent to reassess whether including TP53 in Table 1 is appropriate.

Authors’ reply

Thank you for your suggestions regarding the inclusion of TP53 in Table 1.  Given the potential confusion arising from referencing both a review article and a research article for TP53's roles, and considering the prevalence of TP53 mutations in pancreatic cancer, I agree that it may be appropriate to remove role of TP53 from Table 1.  I will proceed with deleting the role of TP53 from the table accordingly. The table has been reconstructed according to reviewer’s 1 suggestion as well. Thank you for bringing this to our attention.

Comments on the Quality of English Language: Minor editing of the English language is required.

Authors’ reply

Thank you very much for your comment. We did revise the paper and corrected all the spelling mistakes.