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Association of PIK3CA mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma |
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| Author: | Ugai, Tomotaka1,2; Zhao, Melissa1; Shimizu, Takashi3; |
| Organizations: |
1Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 3Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
4Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 6Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA 7Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 8Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA 9Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA 10Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA 11Broad Institute of MIT and Harvard, Cambridge, MA, USA 12Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 13Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland 14Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 2.2 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2021090245034 |
| Language: | English |
| Published: |
Informa,
2021
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| Publish Date: | 2021-09-02 |
| Description: |
AbstractImmunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that PIK3CA mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed PIK3CA mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, KRAS and BRAF mutations. PIK3CA mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22–2.75; P = .004]. PIK3CA mutation was statistically-insignificantly (P = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03–2.31). PIK3CA-mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than PIK3CA-wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) (P = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway. see all
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| Series: |
OncoImmunology |
| ISSN: | 2162-4011 |
| ISSN-E: | 2162-402X |
| ISSN-L: | 2162-4011 |
| Volume: | 10 |
| Issue: | 1 |
| Article number: | 1956173 |
| DOI: | 10.1080/2162402X.2021.1956173 |
| OADOI: | https://oadoi.org/10.1080/2162402X.2021.1956173 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3122 Cancers |
| Subjects: | |
| Funding: |
This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; U01 CA167552 to L.A. Mucci and W.C. Willett; P50 CA127003 to N. Bardeesy and B.M. Wolpin; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; R00 CA215314 to M.S.; and K07 CA188126 to X.Z.); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to S.O.); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; by the American Cancer Society Mentored Research Scholar Grant (MRSG-17-220-01 - NEC to M.S.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K.A. and T.U. were supported by a grant from Overseas Research Fellowship (201860083 to K.A. and 201960541 to T.U.) from Japan Society for the Promotion of Science. K.H. and T.U. were supported by fellowship grants from the Uehara Memorial Foundation. T.U. was supported by fellowship grants from Yasuda Medical Foundation. K.H. was supported by the Mitsukoshi Health and Welfare Foundation. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. J.A.M. research is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, P fund and the George Stone Family Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH;American Association for Cancer Research;Japan Society for the Promotion of Science [201960541];Japan Society for the Promotion of Science;the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, P fund and the George Stone Family Foundation;Mitsukoshi Health and Welfare Foundation;Dana-Farber Harvard Cancer Center;Uehara Memorial Foundation;Uehara Memorial Foundation;Yasuda Memorial Medical Foundation. |
| Copyright information: |
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
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https://creativecommons.org/licenses/by-nc/4.0/ |