The expressed mutational landscape of microsatellite stable colorectal cancers
Abstract Background Colorectal cancer is the 2nd leading cause of cancer-related deaths with few patients benefiting from biomarker-guided therapy. Mutation expression is essential for accurate interpretation of mutations as biomarkers, but surprisingly, little has been done to analyze somatic cance...
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| Format: | Article |
| Language: | English |
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BMC
2021-09-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-021-00955-2 |
| _version_ | 1818716414810259456 |
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| author | Anita Sveen Bjarne Johannessen Ina A. Eilertsen Bård I. Røsok Marie Gulla Peter W. Eide Jarle Bruun Kushtrim Kryeziu Leonardo A. Meza-Zepeda Ola Myklebost Bjørn A. Bjørnbeth Rolf I. Skotheim Arild Nesbakken Ragnhild A. Lothe |
| author_facet | Anita Sveen Bjarne Johannessen Ina A. Eilertsen Bård I. Røsok Marie Gulla Peter W. Eide Jarle Bruun Kushtrim Kryeziu Leonardo A. Meza-Zepeda Ola Myklebost Bjørn A. Bjørnbeth Rolf I. Skotheim Arild Nesbakken Ragnhild A. Lothe |
| author_sort | Anita Sveen |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer is the 2nd leading cause of cancer-related deaths with few patients benefiting from biomarker-guided therapy. Mutation expression is essential for accurate interpretation of mutations as biomarkers, but surprisingly, little has been done to analyze somatic cancer mutations on the expression level. We report a large-scale analysis of allele-specific mutation expression. Methods Whole-exome and total RNA sequencing was performed on 137 samples from 121 microsatellite stable colorectal cancers, including multiregional samples of primary and metastatic tumors from 4 patients. Data were integrated with allele-specific resolution. Results were validated in an independent set of 241 colon cancers. Therapeutic associations were explored by pharmacogenomic profiling of 15 cell lines or patient-derived organoids. Results The median proportion of expressed mutations per tumor was 34%. Cancer-critical mutations had the highest expression frequency (gene-wise mean of 58%), independent of frequent allelic imbalance. Systematic deviation from the general pattern of expression levels according to allelic frequencies was detected, including preferential expression of mutated alleles dependent on the mutation type and target gene. Translational relevance was suggested by correlations of KRAS/NRAS or TP53 mutation expression levels with downstream oncogenic signatures (p < 0.03), overall survival among patients with stage II and III cancer (KRAS/NRAS: hazard ratio 6.1, p = 0.0070), and targeted drug sensitivity. The latter was demonstrated for EGFR and MDM2 inhibition in pre-clinical models. Conclusions Only a subset of mutations in microsatellite stable colorectal cancers were expressed, and the “expressed mutation dose” may provide an opportunity for more fine-tuned biomarker interpretations. |
| first_indexed | 2024-12-17T19:18:53Z |
| format | Article |
| id | doaj.art-b34b58a9f5234132b5b1362c2f2bb886 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-17T19:18:53Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-b34b58a9f5234132b5b1362c2f2bb8862022-12-21T21:35:40ZengBMCGenome Medicine1756-994X2021-09-0113111810.1186/s13073-021-00955-2The expressed mutational landscape of microsatellite stable colorectal cancersAnita Sveen0Bjarne Johannessen1Ina A. Eilertsen2Bård I. Røsok3Marie Gulla4Peter W. Eide5Jarle Bruun6Kushtrim Kryeziu7Leonardo A. Meza-Zepeda8Ola Myklebost9Bjørn A. Bjørnbeth10Rolf I. Skotheim11Arild Nesbakken12Ragnhild A. Lothe13Department of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalK.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalDepartment of Tumor Biology, Institute for Cancer Research, Oslo University HospitalDepartment of Tumor Biology, Institute for Cancer Research, Oslo University HospitalK.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalK.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University HospitalDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University HospitalAbstract Background Colorectal cancer is the 2nd leading cause of cancer-related deaths with few patients benefiting from biomarker-guided therapy. Mutation expression is essential for accurate interpretation of mutations as biomarkers, but surprisingly, little has been done to analyze somatic cancer mutations on the expression level. We report a large-scale analysis of allele-specific mutation expression. Methods Whole-exome and total RNA sequencing was performed on 137 samples from 121 microsatellite stable colorectal cancers, including multiregional samples of primary and metastatic tumors from 4 patients. Data were integrated with allele-specific resolution. Results were validated in an independent set of 241 colon cancers. Therapeutic associations were explored by pharmacogenomic profiling of 15 cell lines or patient-derived organoids. Results The median proportion of expressed mutations per tumor was 34%. Cancer-critical mutations had the highest expression frequency (gene-wise mean of 58%), independent of frequent allelic imbalance. Systematic deviation from the general pattern of expression levels according to allelic frequencies was detected, including preferential expression of mutated alleles dependent on the mutation type and target gene. Translational relevance was suggested by correlations of KRAS/NRAS or TP53 mutation expression levels with downstream oncogenic signatures (p < 0.03), overall survival among patients with stage II and III cancer (KRAS/NRAS: hazard ratio 6.1, p = 0.0070), and targeted drug sensitivity. The latter was demonstrated for EGFR and MDM2 inhibition in pre-clinical models. Conclusions Only a subset of mutations in microsatellite stable colorectal cancers were expressed, and the “expressed mutation dose” may provide an opportunity for more fine-tuned biomarker interpretations.https://doi.org/10.1186/s13073-021-00955-2Colorectal cancerExome sequencingRNA sequencingAllele-specific mutation expressionMutant allele fractionPharmacogenomics |
| spellingShingle | Anita Sveen Bjarne Johannessen Ina A. Eilertsen Bård I. Røsok Marie Gulla Peter W. Eide Jarle Bruun Kushtrim Kryeziu Leonardo A. Meza-Zepeda Ola Myklebost Bjørn A. Bjørnbeth Rolf I. Skotheim Arild Nesbakken Ragnhild A. Lothe The expressed mutational landscape of microsatellite stable colorectal cancers Genome Medicine Colorectal cancer Exome sequencing RNA sequencing Allele-specific mutation expression Mutant allele fraction Pharmacogenomics |
| title | The expressed mutational landscape of microsatellite stable colorectal cancers |
| title_full | The expressed mutational landscape of microsatellite stable colorectal cancers |
| title_fullStr | The expressed mutational landscape of microsatellite stable colorectal cancers |
| title_full_unstemmed | The expressed mutational landscape of microsatellite stable colorectal cancers |
| title_short | The expressed mutational landscape of microsatellite stable colorectal cancers |
| title_sort | expressed mutational landscape of microsatellite stable colorectal cancers |
| topic | Colorectal cancer Exome sequencing RNA sequencing Allele-specific mutation expression Mutant allele fraction Pharmacogenomics |
| url | https://doi.org/10.1186/s13073-021-00955-2 |
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