Proteotranscriptomic Analyses of Microsatellite-Stable Early-Onset Colorectal Cancer Article Swipe
Jumanah Alshenaifi
,
Giulia Maddalena
,
Jessica C. Lal
,
Oluwadara Coker
,
Hey Min Lee
,
Oscar E. Villarreal
,
Ganiraju C. Manyam
,
Alaa M. Mohamed
,
Guglielmo Vetere
,
Michael G. White
,
Nadim J. Ajami
,
Preeti Kanikarla Marie
,
Alexey V. Sorokin
,
David G. Menter
,
Y. Nancy You
,
P. Andrew Futreal
,
Scott Kopetz
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1200/oa-24-00090
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1200/oa-24-00090
PURPOSE The prevalence and death rates of early-onset colorectal cancer (EOCRC) have been increasing at an alarming rate since 1994. Compared with late-onset colorectal cancer (LOCRC), EOCRC is more aggressive and resistant to treatment. Despite KRAS mutations and the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway's significant role in colorectal cancer tumorigenesis and progression, these mutations are less frequent in patients with EOCRC. METHODS In this study, we conducted proteotranscriptomic profiling of two independent cohorts (MD Anderson for testing and The Cancer Genome Atlas for validation), comparing EOCRC and LOCRC tumors. Our focus was on sporadic, microsatellite-stable, treatment-naïve patients with early-onset (60 years) colorectal adenocarcinomas. RESULTS Our analysis revealed consistent molecular differences between EOCRC and LOCRC, particularly in pathway enrichment profiles. The two pathways with the highest levels of significant gene set enrichment analysis in EOCRC tumors were the downregulation of epithelial-mesenchymal transition and upregulation of Wnt/β-catenin signaling pathways. Both testing and validation cohorts showed a consistent enrichment in hallmark KRAS signaling. However, using the novel KRAS-ERK gene signatures to better capture the pathway signaling functionality, we identified a consistent upregulation of MAPK signaling specifically in EOCRC tumors. Further analysis of this enrichment in wild-type RAS GTPase ( KRAS , NRAS , and HRAS ) tumors confirmed significant MAPK upregulation in EOCRC wild-type RAS tumors ( P < .001). Proteomic analysis further supported these transcriptomic findings, reinforcing the molecular distinctions in EOCRC. CONCLUSION This study not only elucidates the unique molecular attributes of EOCRC but also lays the groundwork for exploring MAPK-targeted therapies specifically for this age group. Given the increasing prevalence of EOCRC, our findings highlight the need for larger investigations into MAPK upregulation in EOCRC and its potential as a target for precision therapies.
Related Topics
Concepts
Colorectal cancer
Microsatellite
Medicine
Oncology
Microsatellite instability
Internal medicine
Biology
Genetics
Cancer
Allele
Gene
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1200/oa-24-00090
- OA Status
- diamond
- References
- 87
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4413637718
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4413637718Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1200/oa-24-00090Digital Object Identifier
- Title
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Proteotranscriptomic Analyses of Microsatellite-Stable Early-Onset Colorectal CancerWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-08-01Full publication date if available
- Authors
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Jumanah Alshenaifi, Giulia Maddalena, Jessica C. Lal, Oluwadara Coker, Hey Min Lee, Oscar E. Villarreal, Ganiraju C. Manyam, Alaa M. Mohamed, Guglielmo Vetere, Michael G. White, Nadim J. Ajami, Preeti Kanikarla Marie, Alexey V. Sorokin, David G. Menter, Y. Nancy You, P. Andrew Futreal, Scott KopetzList of authors in order
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https://doi.org/10.1200/oa-24-00090Publisher landing page
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YesWhether a free full text is available
- OA status
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diamondOpen access status per OpenAlex
- OA URL
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https://doi.org/10.1200/oa-24-00090Direct OA link when available
- Concepts
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Colorectal cancer, Microsatellite, Medicine, Oncology, Microsatellite instability, Internal medicine, Biology, Genetics, Cancer, Allele, GeneTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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87Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.elucidates | 241 |
| abstract_inverted_index.enrichment | 123, 136, 161, 196 |
| abstract_inverted_index.groundwork | 252 |
| abstract_inverted_index.identified | 181 |
| abstract_inverted_index.increasing | 13, 264 |
| abstract_inverted_index.late-onset | 22, 104 |
| abstract_inverted_index.prevalence | 2, 265 |
| abstract_inverted_index.signaling. | 165 |
| abstract_inverted_index.signatures | 172 |
| abstract_inverted_index.therapies. | 289 |
| abstract_inverted_index.transition | 146 |
| abstract_inverted_index.treatment. | 33 |
| abstract_inverted_index.validation | 156 |
| abstract_inverted_index.differences | 115 |
| abstract_inverted_index.early-onset | 7, 100 |
| abstract_inverted_index.independent | 73 |
| abstract_inverted_index.reinforcing | 230 |
| abstract_inverted_index.significant | 46, 133, 211 |
| abstract_inverted_index.distinctions | 233 |
| abstract_inverted_index.particularly | 120 |
| abstract_inverted_index.progression, | 53 |
| abstract_inverted_index.specifically | 188, 257 |
| abstract_inverted_index.upregulation | 148, 184, 213, 278 |
| abstract_inverted_index.validation), | 85 |
| abstract_inverted_index.MAPK-targeted | 255 |
| abstract_inverted_index.tumorigenesis | 51 |
| abstract_inverted_index.Wnt/β-catenin | 150 |
| abstract_inverted_index.downregulation | 143 |
| abstract_inverted_index.functionality, | 179 |
| abstract_inverted_index.investigations | 275 |
| abstract_inverted_index.signal-related | 42 |
| abstract_inverted_index.transcriptomic | 228 |
| abstract_inverted_index.adenocarcinomas. | 108 |
| abstract_inverted_index.treatment-naïve | 97 |
| abstract_inverted_index.mitogen-activated | 39 |
| abstract_inverted_index.kinase/extracellular | 41 |
| abstract_inverted_index.proteotranscriptomic | 69 |
| abstract_inverted_index.epithelial-mesenchymal | 145 |
| abstract_inverted_index.microsatellite-stable, | 96 |
| cited_by_percentile_year | |
| countries_distinct_count | 2 |
| institutions_distinct_count | 17 |
| citation_normalized_percentile.value | 0.50819767 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |