In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries
Introduction: The Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) includes almost 40% TP53-mutants encompassing missense and truncated variants. TCGA revealed ‘POLE’, characterized by POLE gene bearing exonuclease domain mutation (EDM), as the prognostically best molecular profile. T...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Gynecologic Oncology Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352578923000784 |
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| author | Damayanti Das Ghosh Rahul Roy Chowdhury Rajeswari Dutta Indranil Mukhopadhyay Asima Mukhopadhyay Susanta Roychoudhury |
| author_facet | Damayanti Das Ghosh Rahul Roy Chowdhury Rajeswari Dutta Indranil Mukhopadhyay Asima Mukhopadhyay Susanta Roychoudhury |
| author_sort | Damayanti Das Ghosh |
| collection | DOAJ |
| description | Introduction: The Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) includes almost 40% TP53-mutants encompassing missense and truncated variants. TCGA revealed ‘POLE’, characterized by POLE gene bearing exonuclease domain mutation (EDM), as the prognostically best molecular profile. The worst profile was characterized by TP53-mutated Type 2 cancer requiring adjuvant therapy having cost implications in low-resource settings. We aimed to find more ‘POLE-like’ favourable subgroups by searching TCGA cohort, especially within TP53 mutated risk group, that could eventually avoid adjuvant treatment in resource-poor settings. Method: Our study was an in-silico survival analysis performed on the TCGA-UCEC dataset using SPSS statistical package. TP53 and POLE mutations, microsatellite instability (MSI), time-to-event and clinicopathological parameters were compared among 512 endometrial cancer cases. Deleterious POLE-mutations were identified by Polyphen2. Progression free survival was studied using Kaplan-Meier plots keeping original ‘POLE’ as comparator. Result: In presence of wild type (WT)-TP53, other deleterious POLE-mutations behaved like POLE-EDM. Only truncated and not missense TP53 benefitted from POLE/MSI overlap. However, TP53 missense mutation, Y220C, was found to be as favourable as ‘POLE’. Overlapping POLE, MSI and WT-TP53 also performed favourably. Truncated TP53 overlapped with POLE and/or MSI, TP53 Y220C alone and, WT-TP53 overlapped with POLE and MSI both, were named ‘POLE-like’ for prognostically behaving like the comparator ‘POLE’. Conclusion: Obesity being a lesser frequent event in low and middle-income countries (LMICs), relative proportion of women with lower BMI and Type 2 endometrial cancers may be high. Identification of ‘POLE-like’ groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC. |
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| id | doaj.art-dda681eb234448c4872812dc730aefeb |
| institution | Directory Open Access Journal |
| issn | 2352-5789 |
| language | English |
| last_indexed | 2024-03-13T05:02:11Z |
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| series | Gynecologic Oncology Reports |
| spelling | doaj.art-dda681eb234448c4872812dc730aefeb2023-06-17T05:19:21ZengElsevierGynecologic Oncology Reports2352-57892023-06-0147101209In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countriesDamayanti Das Ghosh0Rahul Roy Chowdhury1Rajeswari Dutta2Indranil Mukhopadhyay3Asima Mukhopadhyay4Susanta Roychoudhury5Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India; Kolkata Gynecological Oncology Trials and Translational Research Group, Kolkata, India; Corresponding author at: Department of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata 700063, India. Kolkata Gynecological Oncology Trials and Translational Research Group, Kolkata 700026, India.Department of Gynecological Oncology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India; Kolkata Gynecological Oncology Trials and Translational Research Group, Kolkata, IndiaDepartment of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, IndiaHuman Genetics Unit, Indian Statistical Institute, Kolkata, IndiaKolkata Gynecological Oncology Trials and Translational Research Group, Kolkata, IndiaDepartment of Basic and Translational Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India; Kolkata Gynecological Oncology Trials and Translational Research Group, Kolkata, IndiaIntroduction: The Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) includes almost 40% TP53-mutants encompassing missense and truncated variants. TCGA revealed ‘POLE’, characterized by POLE gene bearing exonuclease domain mutation (EDM), as the prognostically best molecular profile. The worst profile was characterized by TP53-mutated Type 2 cancer requiring adjuvant therapy having cost implications in low-resource settings. We aimed to find more ‘POLE-like’ favourable subgroups by searching TCGA cohort, especially within TP53 mutated risk group, that could eventually avoid adjuvant treatment in resource-poor settings. Method: Our study was an in-silico survival analysis performed on the TCGA-UCEC dataset using SPSS statistical package. TP53 and POLE mutations, microsatellite instability (MSI), time-to-event and clinicopathological parameters were compared among 512 endometrial cancer cases. Deleterious POLE-mutations were identified by Polyphen2. Progression free survival was studied using Kaplan-Meier plots keeping original ‘POLE’ as comparator. Result: In presence of wild type (WT)-TP53, other deleterious POLE-mutations behaved like POLE-EDM. Only truncated and not missense TP53 benefitted from POLE/MSI overlap. However, TP53 missense mutation, Y220C, was found to be as favourable as ‘POLE’. Overlapping POLE, MSI and WT-TP53 also performed favourably. Truncated TP53 overlapped with POLE and/or MSI, TP53 Y220C alone and, WT-TP53 overlapped with POLE and MSI both, were named ‘POLE-like’ for prognostically behaving like the comparator ‘POLE’. Conclusion: Obesity being a lesser frequent event in low and middle-income countries (LMICs), relative proportion of women with lower BMI and Type 2 endometrial cancers may be high. Identification of ‘POLE-like’ groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC.http://www.sciencedirect.com/science/article/pii/S2352578923000784Endometrial cancerTCGATP53POLE-likePrognosisLow and middle-income countries |
| spellingShingle | Damayanti Das Ghosh Rahul Roy Chowdhury Rajeswari Dutta Indranil Mukhopadhyay Asima Mukhopadhyay Susanta Roychoudhury In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries Gynecologic Oncology Reports Endometrial cancer TCGA TP53 POLE-like Prognosis Low and middle-income countries |
| title | In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries |
| title_full | In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries |
| title_fullStr | In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries |
| title_full_unstemmed | In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries |
| title_short | In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries |
| title_sort | in silico analysis of tcga data showing multiple pole like favourable subgroups overlapping with tp53 mutated endometrial cancer implications for clinical practice in low and middle income countries |
| topic | Endometrial cancer TCGA TP53 POLE-like Prognosis Low and middle-income countries |
| url | http://www.sciencedirect.com/science/article/pii/S2352578923000784 |
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