التفاصيل البيبلوغرافية
| العنوان: |
Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer |
| المؤلفون: |
Jørgen Smeby, Anita Sveen, Christian H Bergsland, Ina A Eilertsen, Stine A Danielsen, Peter W Eide, Merete Hektoen, Marianne G Guren, Arild Nesbakken, Jarle Bruun, Ragnhild A Lothe |
| المصدر: |
ESMO Open, Vol 4, Iss 3 (2019) |
| بيانات النشر: |
Elsevier, 2019. |
| سنة النشر: |
2019 |
| المجموعة: |
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: |
Background Accumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC).Materials and methods In a single-hospital series of 401 stage I–IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582).Results TP53 mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2−4>0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028).Conclusions Integration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2059-7029 |
| Relation: |
https://esmoopen.bmj.com/content/4/3/e000523.full; https://doaj.org/toc/2059-7029 |
| DOI: |
10.1136/esmoopen-2019-000523 |
| URL الوصول: |
https://doaj.org/article/05bcd7e2b72546499946ebcd3fa96bbd |
| رقم الانضمام: |
edsdoj.05bcd7e2b72546499946ebcd3fa96bbd |
| قاعدة البيانات: |
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