Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: LeveragingLarge-ScaleData to Inform Therapeutic Directions

Background We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. Methods Using comprehensive genomic profiling (315 genes, >500x coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4amplification,CDK6amplification,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 (RB1andCCNE1). 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 includedCDKN2A(13.9%) andCDKN2Bloss (12.5%). Examples of unique patterns of alterations includedCCND1amplification in breast cancer (17.3%);CDK4alterations in sarcomas (12%);CCND2in testicular cancer (23.4%), andSMARCB1mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genesRB1andCCNE1affected 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.ARand cyclin activating/sensitizing alterations in prostate cancer co-occurred more frequently (vs.ARalterations and wild-type cyclin activating/sensitizing alterations) (OR, 1.79;p< .001) as didESR1and cyclin activating/sensitizing alterations in breast (OR, 1.62;p< .001) and cervical cancer (OR, 4.08;p= .04) (vs.ESR1and 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.

Automated summary

The study revealed high frequencies of alterations in cyclin and related gene pathways in solid tumors, with significant variations depending on tumor types and histological subtypes, suggesting opportunities for targeted therapy.