The prognostic, predictive and clinicopathological impact of KRT81 / HNF1A- and GATA6- based transcriptional subtyping in pancreatic cancer
medrxiv(2024)
摘要
BACKGROUND Transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) have prognostic implications and potential predictive functions. This study aimed to determine their clinicopathological impact in large cohorts of advanced and resected PDAC and their evolution during disease progression. METHODS The clinicopathological and prognostic implications of transcriptional subtypes determined by the expression of KRT81, HNF1A and GATA6 were examined using immunohistochemistry in advanced (n=139) and resected (n=411) PDAC samples as well as in 57 matched primary tumors and corresponding metastases. RNAseq data of 316 resected PDAC patients was analyzed for validation. RESULTS Both subtyping systems were highly interrelated. Subtypes switched during disease progression in up to 31.6% of patients. Transcriptional subtyping had a modest prognostic impact in both unstratified cohorts, but strongly improved outcomes in patients with KRT81 positive / GATA6 negative tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings. CONCLUSIONS Transcriptional subtypes have differential responses on palliative and adjuvant gemcitabine-based chemotherapy, but they may change during disease progression. Both employed subtyping systems are equivalent and can be used to inform clinical therapy decisions. CLINICAL TRIAL REGISTRY The clinical trial registry identifier is [NCT00440167][1].
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
This study did not receive any funding
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Each patient gave written informed consent for the use of its tumor material and clinical data for academic research purposes upon study enrollment. Ethical approval by the local ethics committee was given for each study 33,34 and they were carried out according to the Declaration of Helsinki. The non-commercial academic use of anonymized patient data and corresponding tumor material was approved by the ethics committee of the medical faculty of Ludwig-Maximilians-University without obtaining the patients' informed consent (project numbers 554-11, 401-15, 20-081, 23-0222 and 23-0224).
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
The expression datasets used for validation are publicly accessible on https://portal.gdc.cancer.gov/ and https://dcc.icgc.org/. Raw data on the patient cohorts employed in this study can be obtained from the corresponding author upon reasonable request.
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00440167&atom=%2Fmedrxiv%2Fearly%2F2024%2F04%2F30%2F2024.04.29.24306532.atom
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