See the published version of this preprint at Diagnostic Pathology.
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Research
Mi Jung Kwon
Hallym University Sacred Heart Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2441-0448
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1), which is essential for immune evasion, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target. PIK3CA, KRAS, and BRAF mutations, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR), and human papillomavirus (HPV) can potentially upregulate PD-L1 expression, which might contribute to the clinical outcome of patients with ESCC.
Methods: We investigated the significance of the present druggable markers [PD-L1, PIK3CA, KRAS, and BRAF mutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS, BRAF, and PIK3CA mutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers.
Results: PD-L1 expression, PIK3CA mutation, and MSI/dMMR were detected in 35.9%, 12.5%, and 17.2% of ESCCs, respectively. HPV was rarely detected (1.6%) (high-risk HPV68), whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P>0.05). PD-L1, PIK3CA mutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (all P<0.05). In multivariate analysis, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P=0.023, P=0.014). In the PD-L1-negative ESCCs, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P=0.006, P=0.002).
Conclusions: PIK3CA mutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.
Keywords
Programmed death-ligand 1, Esophagus, Squamous cell carcinoma, Microsatellite instability, Human papillomavirus, PIK3CA.
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CURRENT STATUS: Published
View the published article at Diagnostic Pathology.
Version 2
Posted 18 Sep, 2020
No community comments so far
Editorial decision: Accept
On 04 Oct, 2020
Review #2 received
Received 17 Sep, 2020
Reviewer #1 agreed
On 17 Sep, 2020
Reviewer #2 agreed
On 17 Sep, 2020
Review #1 received
Received 17 Sep, 2020
Reviewers invited
Invitations sent on 16 Sep, 2020
Editor assigned
On 15 Sep, 2020
Submission checks complete
On 14 Sep, 2020
Editor invited
On 14 Sep, 2020
No comments provided
Editorial decision: Minor Revision
On 07 Sep, 2020
Review #2 received
Received 30 Aug, 2020
Reviewer #2 agreed
On 24 Aug, 2020
Review #1 received
Received 12 Aug, 2020
Reviewer #1 agreed
On 29 Jul, 2020
Reviewers invited
Invitations sent on 27 Jul, 2020
Editor assigned
On 20 Jul, 2020
Editor invited
On 19 Jul, 2020
Submission checks complete
On 15 Jul, 2020
First submitted
On 13 Jul, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Pathology
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See the published version of this preprint at Diagnostic Pathology.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Mi Jung Kwon
Hallym University Sacred Heart Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2441-0448
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Diagnostic Pathology.
Version 2
Posted 18 Sep, 2020
No community comments so far
Editorial decision: Accept
On 04 Oct, 2020
Review #2 received
Received 17 Sep, 2020
Reviewer #1 agreed
On 17 Sep, 2020
Reviewer #2 agreed
On 17 Sep, 2020
Review #1 received
Received 17 Sep, 2020
Reviewers invited
Invitations sent on 16 Sep, 2020
Editor assigned
On 15 Sep, 2020
Submission checks complete
On 14 Sep, 2020
Editor invited
On 14 Sep, 2020
No comments provided
Editorial decision: Minor Revision
On 07 Sep, 2020
Review #2 received
Received 30 Aug, 2020
Reviewer #2 agreed
On 24 Aug, 2020
Review #1 received
Received 12 Aug, 2020
Reviewer #1 agreed
On 29 Jul, 2020
Reviewers invited
Invitations sent on 27 Jul, 2020
Editor assigned
On 20 Jul, 2020
Editor invited
On 19 Jul, 2020
Submission checks complete
On 15 Jul, 2020
First submitted
On 13 Jul, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Pathology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Diagnostic Pathology.
Background: Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1), which is essential for immune evasion, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target. PIK3CA, KRAS, and BRAF mutations, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR), and human papillomavirus (HPV) can potentially upregulate PD-L1 expression, which might contribute to the clinical outcome of patients with ESCC.
Methods: We investigated the significance of the present druggable markers [PD-L1, PIK3CA, KRAS, and BRAF mutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS, BRAF, and PIK3CA mutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers.
Results: PD-L1 expression, PIK3CA mutation, and MSI/dMMR were detected in 35.9%, 12.5%, and 17.2% of ESCCs, respectively. HPV was rarely detected (1.6%) (high-risk HPV68), whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P>0.05). PD-L1, PIK3CA mutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (all P<0.05). In multivariate analysis, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P=0.023, P=0.014). In the PD-L1-negative ESCCs, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P=0.006, P=0.002).
Conclusions: PIK3CA mutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.
Figure 1
Figure 2
Figure 3
This is a list of supplementary files associated with this preprint. Click to download.
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