Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.
Adenocarcinoma, Clear Cell
/ enzymology
Age Factors
Biomarkers, Tumor
/ biosynthesis
Carcinoma, Ovarian Epithelial
/ enzymology
Cohort Studies
Down-Regulation
Female
Gene Knockout Techniques
Humans
Middle Aged
Neoplasm Staging
Ovarian Neoplasms
/ enzymology
PTEN Phosphohydrolase
/ biosynthesis
Prospective Studies
Receptors, Androgen
/ biosynthesis
Receptors, Estrogen
/ biosynthesis
Receptors, Progesterone
/ biosynthesis
Tissue Array Analysis
Tumor Suppressor Proteins
/ biosynthesis
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
01
01
2020
accepted:
29
04
2020
revised:
14
03
2020
pubmed:
20
6
2020
medline:
1
4
2021
entrez:
20
6
2020
Statut:
ppublish
Résumé
PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Sections du résumé
BACKGROUND
PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.
METHODS
Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.
RESULTS
Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).
CONCLUSIONS
PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Identifiants
pubmed: 32555365
doi: 10.1038/s41416-020-0900-0
pii: 10.1038/s41416-020-0900-0
pmc: PMC7463007
doi:
Substances chimiques
AR protein, human
0
Biomarkers, Tumor
0
Receptors, Androgen
0
Receptors, Estrogen
0
Receptors, Progesterone
0
Tumor Suppressor Proteins
0
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
Types de publication
Journal Article
Multicenter Study
Observational Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
793-802Subventions
Organisme : Cancer Research UK
ID : 15601
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12023/20
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA071789
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA159981
Pays : United States
Références
Vaughan, S., Coward, J. I., Bast, R. C. Jr., Berchuck, A., Berek, J. S., Brenton, J. D. et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer 11, 719–725 (2011).
doi: 10.1038/nrc3144
Bowtell, D. D., Bohm, S., Ahmed, A. A., Aspuria, P. J., Bast, R. C. Jr., Beral, V. et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer 15, 668–679 (2015).
doi: 10.1038/nrc4019
Lee, Y. R., Chen, M. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat. Rev. Mol. Cell Biol. 19, 547–562 (2018).
doi: 10.1038/s41580-018-0015-0
Peng, W., Chen, J. Q., Liu, C., Malu, S., Creasy, C., Tetzlaff, M. T. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).
doi: 10.1158/2159-8290.CD-15-0283
Guzeloglu-Kayisli, O., Kayisli, U. A., Al-Rejjal, R., Zheng, W., Luleci, G. & Arici, A. Regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression by estradiol and progesterone in human endometrium. J. Clin. Endocrinol. Metab. 88, 5017–5026 (2003).
doi: 10.1210/jc.2003-030414
McConechy, M. K., Ding, J., Senz, J., Yang, W., Melnyk, N., Tone, A. A. et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod. Pathol. 27, 128–134 (2014).
doi: 10.1038/modpathol.2013.107
Obata, K., Morland, S. J., Watson, R. H., Hitchcock, A., Chenevix-Trench, G., Thomas, E. J. et al. Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res. 58, 2095–2097 (1998).
pubmed: 9605750
Sato, N., Tsunoda, H., Nishida, M., Morishita, Y., Takimoto, Y., Kubo, T. et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 60, 7052–7056 (2000).
pubmed: 11156411
Kurman, R. J. & Shih, Ie. M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum. Pathol. 42, 918–931 (2011).
doi: 10.1016/j.humpath.2011.03.003
Hauke, J., Hahnen, E., Schneider, S., Reuss, A., Richters, L., Kommoss, S. et al. Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883). J. Med. Genet. 56, 574–580 (2019).
doi: 10.1136/jmedgenet-2018-105930
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
Kim, J., Coffey, D. M., Creighton, C. J., Yu, Z., Hawkins, S. M. & Matzuk, M. M. High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc. Natl Acad. Sci. USA 109, 3921–3926 (2012).
doi: 10.1073/pnas.1117135109
Perets, R., Wyant, G. A., Muto, K. W., Bijron, J. G., Poole, B. B., Chin, K. T. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751–765 (2013).
doi: 10.1016/j.ccr.2013.10.013
Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D. & Jacks, T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat. Med. 11, 63–70 (2005).
doi: 10.1038/nm1173
Martins, F. C., Santiago, I., Trinh, A., Xian, J., Guo, A., Sayal, K. et al. Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier. Genome Biol. 15, 526 (2014).
doi: 10.1186/s13059-014-0526-8
Goode, E. L., Block, M. S., Kalli, K. R., Vierkant, R. A., Chen, W., Fogarty, Z. C. et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 3, e173290 (2017).
doi: 10.1001/jamaoncol.2017.3290
Sieh, W., Kobel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T. et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis Consortium study. Lancet Oncol. 14, 853–862 (2013).
doi: 10.1016/S1470-2045(13)70253-5
Martins, F. C., De, S., Almendro, V., Gonen, M., Park, S. Y., Blum, J. L. et al. Evolutionary pathways in BRCA1-associated breast tumors. Cancer Discov. 2, 503–511 (2012).
doi: 10.1158/2159-8290.CD-11-0325
Agresti, A. Categorical Data Analysis (John Wiley & Sons, 2002).
Carver, B. S., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).
doi: 10.1016/j.ccr.2011.04.008
Buuren, S. V. Flexible Imputation of Missing Data (Chapman & Hall/CRC, 2012).
Bretz, F., Hothorn, T. & Westfall, P. Multiple Comparisons Using R (Chapman & Hall/CRC, 2010).
Landis, J. R. & Koch, G. G. The measurement of observer agreement for categorical data. Biometrics 33, 159–174 (1977).
doi: 10.2307/2529310
Shen, W. H., Balajee, A. S., Wang, J., Wu, H., Eng, C., Pandolfi, P. P. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).
doi: 10.1016/j.cell.2006.11.042
Roh, M. H., Yassin, Y., Miron, A., Mehra, K. K., Mehrad, M., Monte, N. M. et al. High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression. Mod. Pathol. 23, 1316–1324 (2010).
doi: 10.1038/modpathol.2010.119
Tomasetti, C., Marchionni, L., Nowak, M. A., Parmigiani, G. & Vogelstein, B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc. Natl Acad. Sci. USA 112, 118–123 (2015).
doi: 10.1073/pnas.1421839112
Eckert, M. A., Pan, S., Hernandez, K. M., Loth, R. M., Andrade, J., Volchenboum, S. L. et al. Genomics of ovarian cancer progression reveals diverse metastatic trajectories including intraepithelial metastasis to the fallopian tube. Cancer Discov. 6, 1342–1351 (2016).
doi: 10.1158/2159-8290.CD-16-0607
Labidi-Galy, S. I., Papp, E., Hallberg, D., Niknafs, N., Adleff, V., Noe, M. et al. High grade serous ovarian carcinomas originate in the fallopian tube. Nat. Commun. 8, 1093 (2017).
doi: 10.1038/s41467-017-00962-1
Gorringe, K. L., Jacobs, S., Thompson, E. R., Sridhar, A., Qiu, W., Choong, D. Y. et al. High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin. Cancer Res. 13, 4731–4739 (2007).
doi: 10.1158/1078-0432.CCR-07-0502
Chow, R. D., Guzman, C. D., Wang, G., Schmidt, F., Youngblood, M. W., Ye, L. et al. AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma. Nat. Neurosci. 20, 1329–1341 (2017).
doi: 10.1038/nn.4620
Berenjeno, I. M., Pineiro, R., Castillo, S. D., Pearce, W., McGranahan, N., Dewhurst, S. M. et al. Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nat. Commun. 8, 1773 (2017).
doi: 10.1038/s41467-017-02002-4
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
doi: 10.1126/scisignal.2004088
Patch, A. M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).
doi: 10.1038/nature14410
Pearce, C. L., Templeman, C., Rossing, M. A., Lee, A., Near, A. M., Webb, P. M. et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 13, 385–394 (2012).
doi: 10.1016/S1470-2045(11)70404-1
Suda, K., Nakaoka, H., Yoshihara, K., Ishiguro, T., Tamura, R., Mori, Y. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 24, 1777–1789 (2018).
doi: 10.1016/j.celrep.2018.07.037
Mulholland, D. J., Tran, L. M., Li, Y., Cai, H., Morim, A., Wang, S. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011).
doi: 10.1016/j.ccr.2011.05.006
Choi, J. P., Desai, R., Zheng, Y., Yao, M., Dong, Q., Watson, G. et al. Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer. Endocr. Relat. Cancer 22, 687–701 (2015).
doi: 10.1530/ERC-15-0203
Dillon, L. M. & Miller, T. W. Therapeutic targeting of cancers with loss of PTEN function. Curr. Drug Targets 15, 65–79 (2014).
doi: 10.2174/1389450114666140106100909
McGrail, D. J., Federico, L., Li, Y., Dai, H., Lu, Y., Mills, G. B. et al. Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers. Nat. Commun. 9, 1317 (2018).
doi: 10.1038/s41467-018-03730-x
Press, J. Z., De Luca, A., Boyd, N., Young, S., Troussard, A., Ridge, Y. et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 8, 17 (2008).
doi: 10.1186/1471-2407-8-17
Vidotto, T., Saggioro, F. P., Jamaspishvili, T., Chesca, D. L., Picanco de Albuquerque, C. G., Reis, R. B. et al. PTEN-deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells. Prostate 79, 969–979 (2019).
doi: 10.1002/pros.23808
Zhang, J., Gao, X., Schmit, F., Adelmant, G., Eck, M. J., Marto, J. A. et al. CRKL mediates p110beta-dependent PI3K signaling in PTEN-deficient cancer cells. Cell Rep. 20, 549–557 (2017).
doi: 10.1016/j.celrep.2017.06.054
Zervantonakis, I. K., Iavarone, C., Chen, H. Y., Selfors, L. M., Palakurthi, S., Liu, J. F. et al. Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response. Nat. Commun. 8, 365 (2017).
doi: 10.1038/s41467-017-00263-7
Philip, C. A., Laskov, I., Beauchamp, M. C., Marques, M., Amin, O., Bitharas, J. et al. Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer 17, 638 (2017).
doi: 10.1186/s12885-017-3639-0