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Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic
Denis L Jardim1, Sherri Z Millis2, Jeffrey S Ross2
1Department of Clinical Oncology, Hospital Sirio Libanes, São Paulo, Brazil.
Background:
We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.
Methods:
Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co-alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1).
Results:
Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co-occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co-occurred more frequently (vs. AR alterations and wild-type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild-type activating/sensitizing alterations).
Conclusion:
Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers.
Implications For Practice:
Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.
Insights
Genomic alterations in cyclin-related genes are common across many solid tumors, varying by cancer type. Comprehensive profiling reveals potential for targeted therapies, even in rare cancers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Cyclin gene pathway alterations are implicated in tumorigenesis.
- Understanding these alterations is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the landscape of cyclin and interactive gene pathway alterations in a large cohort of solid tumors.
- To identify specific cyclin pathway alterations and their co-occurrence with hormone receptor and resistance genes.
Main Methods:
- Comprehensive genomic profiling of 315 genes in 190,247 solid tumor samples.
- Analysis of alterations in cyclin-activating/sensitizing genes, hormone receptor genes (ESR1, AR), and resistance genes (RB1, CCNE1).
Main Results:
- Cyclin pathway alterations occurred in 24% of malignancies, with high frequencies in brain gliomas, esophageal, bladder, and mesothelioma.
- Specific alterations like CDKN2A/B loss, CCND1 amplification in breast cancer, CDK4 in sarcomas, and SMARCB1 in kidney cancer were identified.
- Co-occurrence analysis revealed complex interactions between cyclin pathway alterations and hormone receptor genes in specific cancer types.
Conclusions:
- Cyclin pathway genomic abnormalities are prevalent in solid tumors and exhibit significant variation by tumor type and histology.
- Comprehensive profiling of the cyclin pathway offers opportunities for targeted therapeutic strategies, including for rare cancers.
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