A 10-gene prognostic signature points to LIMCH1 and HLA-DQB1 as important players in aggressive cervical cancer disease.
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
/ genetics
Carcinoma, Squamous Cell
/ diagnosis
Cohort Studies
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
HLA-DQ beta-Chains
/ genetics
Humans
LIM Domain Proteins
/ genetics
Middle Aged
Neoplasm Invasiveness
Prognosis
Survival Analysis
Transcriptome
Uterine Cervical Neoplasms
/ diagnosis
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
22
12
2020
accepted:
03
02
2021
revised:
26
01
2021
pubmed:
17
3
2021
medline:
16
12
2021
entrez:
16
3
2021
Statut:
ppublish
Résumé
Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.
Sections du résumé
BACKGROUND
Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease.
METHODS
Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort.
RESULTS
Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ).
CONCLUSIONS
This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.
Identifiants
pubmed: 33723390
doi: 10.1038/s41416-021-01305-0
pii: 10.1038/s41416-021-01305-0
pmc: PMC8110544
doi:
Substances chimiques
Biomarkers, Tumor
0
HLA-DQ beta-Chains
0
HLA-DQB1 antigen
0
LIM Domain Proteins
0
LIMCH1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1690-1698Références
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
pubmed: 30207593
Waggoner, S. E. Cervical cancer. Lancet 361, 2217–2225 (2003).
pubmed: 12842378
doi: 10.1016/S0140-6736(03)13778-6
Marth, C., Landoni, F., Mahner, S., McCormack, M., Gonzalez-Martin, A., Colombo, N. et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 28, iv72–iv83 (2017).
pubmed: 28881916
doi: 10.1093/annonc/mdx220
Long, HarryJ. III, Bundy, B. N., Grendys, EdwardC. Jr, Benda, J. A., McMeekin, D. S., Sorosky, J. et al. Randomized Phase III Trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J. Clin. Oncol. 23, 4626–4633 (2005).
pubmed: 15911865
doi: 10.1200/JCO.2005.10.021
Moore, D. H., Blessing, J. A., McQuellon, R. P., Thaler, H. T., Cella, D., Benda, J. et al. Phase III Study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. J. Clin. Oncol. 22, 3113–3119 (2004).
pubmed: 15284262
doi: 10.1200/JCO.2004.04.170
Monk, B. J., Sill, M. W., McMeekin, D. S., Cohn, D. E., Ramondetta, L. M., Boardman, C. H. et al. Phase III Trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group Study. J. Clin. Oncol. 27, 4649–4655 (2009).
pubmed: 19720909
pmcid: 2754911
doi: 10.1200/JCO.2009.21.8909
Tewari, K. S., Sill, M. W., Penson, R. T., Huang, H., Ramondetta, L. M., Landrum, L. M. et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 390, 1654–1663 (2017).
pubmed: 28756902
pmcid: 5714293
doi: 10.1016/S0140-6736(17)31607-0
Chung, H. C., Ros, W., Delord, J. P., Perets, R., Italiano, A., Shapira-Frommer, R. et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the Phase II KEYNOTE-158 Study. J. Clin. Oncol. 37, 1470–1478 (2019).
pubmed: 30943124
doi: 10.1200/JCO.18.01265
Naumann, R. W., Hollebecque, A., Meyer, T., Devlin, M.-J., Oaknin, A., Kerger, J. et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the Phase I/II CheckMate 358 Trial. J. Clin. Oncol. 37, 2825–2834 (2019).
pubmed: 31487218
pmcid: 6823884
doi: 10.1200/JCO.19.00739
Crafton, S. M. & Salani, R. Beyond chemotherapy: an overview and review of targeted therapy in cervical cancer. Clin. Ther. 38, 449–458 (2016).
pubmed: 26926322
doi: 10.1016/j.clinthera.2016.02.007
Hemmatian, B., Sloman, S. J., Cohen Priva, U. & Sloman, S. A. Think of the consequences: a decade of discourse about same-sex marriage. Behav. Res Methods 51, 1565–1585 (2019).
pubmed: 30859479
doi: 10.3758/s13428-019-01215-3
Cancer Genome Atlas Research N, Albert Einstein College of M, Analytical Biological S, Barretos Cancer H, Baylor College of M, Beckman Research Institute of City of H. et al. Integrated genomic and molecular characterization of cervical cancer. Nature 543, 378–384 (2017).
doi: 10.1038/nature21386
Wallbillich, J. J., Tran, P. M., Bai, S., Tran, L. K., Sharma, A. K., Ghamande, S. A. et al. Identification of a transcriptomic signature with excellent survival prediction for squamous cell carcinoma of the cervix. Am. J. Cancer Res. 10, 1534–1547 (2020).
pubmed: 32509396
pmcid: 7269782
Qin, S., Liao, Y., Du, Q., Wang, W., Huang, J., Liu, P. et al. DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer. Cancer Cell Int. 20, 206 (2020).
pubmed: 32514251
pmcid: 7268232
doi: 10.1186/s12935-020-01292-x
Cai, S., Yu, X., Gu, Z., Yang, Q., Wen, B., Sheng, J. et al. A 10-gene prognostic methylation signature for stage I-III cervical cancer. Arch. Gynecol. Obstet. 301, 1275–1287 (2020).
pubmed: 32274635
doi: 10.1007/s00404-020-05524-3
Halle, M. K., Ojesina, A. I., Engerud, H., Woie, K., Tangen, I. L., Holst, F. et al. Clinicopathologic and molecular markers in cervical carcinoma: a prospective cohort study. Am. J. Obstet. Gynecol. 217, 432.e1–e17 (2017).
doi: 10.1016/j.ajog.2017.05.068
Ojesina, A. I., Lichtenstein, L., Freeman, S. S., Pedamallu, C. S., Imaz-Rosshandler, I., Pugh, T. J. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014).
pubmed: 24390348
doi: 10.1038/nature12881
Stefansson, I. M., Salvesen, H. B. & Akslen, L. A. Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J. Clin. Oncol. 22, 1242–1252 (2004).
pubmed: 15051772
doi: 10.1200/JCO.2004.09.034
Kononen, J., Bubendorf, L., Kallioniemi, A., Barlund, M., Schraml, P., Leighton, S. et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat. Med. 4, 844–847 (1998).
pubmed: 9662379
doi: 10.1038/nm0798-844
Hoos, A., Urist, M. J., Stojadinovic, A., Mastorides, S., Dudas, M. E., Leung, D. H. et al. Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am. J. Pathol. 158, 1245–1251 (2001).
pubmed: 11290542
pmcid: 1891917
doi: 10.1016/S0002-9440(10)64075-8
Dysvik, B. & Jonassen, I. J-Express: exploring gene expression data using Java. Bioinformatics 17, 369–370 (2001).
pubmed: 11301307
doi: 10.1093/bioinformatics/17.4.369
Liberzon, A., Birger, C., Thorvaldsdottir, H., Ghandi, M., Mesirov, J. P. & Tamayo, P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
pubmed: 26771021
pmcid: 4707969
doi: 10.1016/j.cels.2015.12.004
Yoshihara, K., Shahmoradgoli, M., Martínez, E., Vegesna, R., Kim, H., Torres-Garcia, W. et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013).
pubmed: 24113773
doi: 10.1038/ncomms3612
Youden, W. J. Index for rating diagnostic tests. Cancer 3, 32–35 (1950).
doi: 10.1002/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3
pubmed: 15405679
Rodig, S. J., Gusenleitner, D., Jackson, D. G., Gjini, E., Giobbie-Hurder, A., Jin, C. et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 10 (2018).
Zhang, Y., Zhang, Y. & Xu, H. LIMCH1 suppress the growth of lung cancer by interacting with HUWE1 to sustain p53 stability. Gene 712, 143963 (2019).
pubmed: 31279706
doi: 10.1016/j.gene.2019.143963
Lin, Y. H., Zhen, Y. Y., Chien, K. Y., Lee, I. C., Lin, W. C., Chen, M. Y. et al. LIMCH1 regulates nonmuscle myosin-II activity and suppresses cell migration. Mol. Biol. Cell 28, 1054–1065 (2017).
pubmed: 28228547
pmcid: 5391182
doi: 10.1091/mbc.e15-04-0218
Cizkova, M., Cizeron-Clairac, G., Vacher, S., Susini, A., Andrieu, C., Lidereau, R. et al. Gene expression profiling reveals new aspects of PIK3CA mutation in ERalpha-positive breast cancer: major implication of the Wnt signaling pathway. PLoS ONE 5, e15647 (2010).
pubmed: 21209903
pmcid: 3012715
doi: 10.1371/journal.pone.0015647
Eckel-Passow, J. E., Serie, D. J., Bot, B. M., Joseph, R. W., Cheville, J. C. & Parker, A. S. ANKS1B is a smoking-related molecular alteration in clear cell renal cell carcinoma. BMC Urol. 14, 14 (2014).
pubmed: 24479813
pmcid: 3944917
doi: 10.1186/1471-2490-14-14
Liu, C., Zhang, Y. H., Huang, T. & Cai, Y. Identification of transcription factors that may reprogram lung adenocarcinoma. Artif. Intell. Med. 83, 52–57 (2017).
pubmed: 28377053
doi: 10.1016/j.artmed.2017.03.010
Chicurel, M. E., Singer, R. H., Meyer, C. J. & Ingber, D. E. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 392, 730–733 (1998).
pubmed: 9565036
doi: 10.1038/33719
Prakash, V., Carson, B. B., Feenstra, J. M., Dass, R. A., Sekyrova, P., Hoshino, A. et al. Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nat. Commun. 10, 2110 (2019).
pubmed: 31068593
pmcid: 6506521
doi: 10.1038/s41467-019-10100-8
Neefjes, J., Jongsma, M. L., Paul, P. & Bakke, O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 11, 823–836 (2011).
pubmed: 22076556
doi: 10.1038/nri3084
Thibodeau, J., Bourgeois-Daigneault, M. C. & Lapointe, R. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology 1, 908–916 (2012).
pubmed: 23162758
pmcid: 3489746
doi: 10.4161/onci.21205
Fujita, H., Suarez-Farinas, M., Mitsui, H., Gonzalez, J., Bluth, M. J., Zhang, S. et al. Langerhans cells from human cutaneous squamous cell carcinoma induce strong type 1 immunity. J. Invest. Dermatol. 132, 1645–1655 (2012).
pubmed: 22402444
pmcid: 3677713
doi: 10.1038/jid.2012.34
Buttice, G., Miller, J., Wang, L. & Smith, B. D. Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells. Circ. Res. 98, 472–479 (2006).
pubmed: 16439692
pmcid: 1388256
doi: 10.1161/01.RES.0000204725.46332.97
Zhang, L., Li, M. X., Deng, B., Dai, N., Feng, Y., Shan, J. L. et al. HLA-DQB1 expression on tumor cells is a novel favorable prognostic factor for relapse in early-stage lung adenocarcinoma. Cancer Manage. Res. 11, 2605–2616 (2019).
doi: 10.2147/CMAR.S197855
Tashiro, H. & Brenner, M. K. Immunotherapy against cancer-related viruses. Cell Res. 27, 59–73 (2017).
pubmed: 28008927
doi: 10.1038/cr.2016.153
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
pubmed: 26028255
pmcid: 4481136
doi: 10.1056/NEJMoa1500596
Tokito, T., Azuma, K., Kawahara, A., Ishii, H., Yamada, K., Matsuo, N. et al. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur. J. Cancer 55, 7–14 (2016).
pubmed: 26771872
doi: 10.1016/j.ejca.2015.11.020
Martens, A., Wistuba-Hamprecht, K., Geukes Foppen, M., Yuan, J., Postow, M. A., Wong, P. et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22, 2908–2918 (2016).
pubmed: 26787752
pmcid: 5770142
doi: 10.1158/1078-0432.CCR-15-2412
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
pubmed: 25409260
pmcid: 4315319
doi: 10.1056/NEJMoa1406498
Johnson, D. B., Estrada, M. V., Salgado, R., Sanchez, V., Doxie, D. B., Opalenik, S. R. et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat. Commun. 7, 10582 (2016).
pubmed: 26822383
pmcid: 4740184
doi: 10.1038/ncomms10582
Johnson, D. B., Nixon, M. J., Wang, Y., Wang, D. Y., Castellanos, E., Estrada, M. V. et al. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight 3 (2018).
Gu, X., Dong, M., Liu, Z., Mi, Y., Yang, J., Zhang, Z. et al. Elevated PD-L1 expression predicts poor survival outcomes in patients with cervical cancer. Cancer Cell Int. 19, 146 (2019).
pubmed: 31143091
pmcid: 6533692
doi: 10.1186/s12935-019-0861-7