Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions

• Published in: The oncologist (Dayton, Ohio) Ohio), 2021-01, Vol.26 (1), p.e78-e89
• Main Authors: Jardim, Denis L., Millis, Sherri Z., Ross, Jeffrey S., Woo, Michelle Sue‐Ann, Ali, Siraj M., Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Cancer; Cancer Diagnostics and Molecular Pathology; Cancer genome; CDK4; CDK6; Cell cycle; Cyclins; Forecasts and trends; Genetic aspects; Genomics; Glioma; Health aspects; Humans; Male; Molecular genetics; Molecular targeted therapy; Mutation; Neoplasms, Germ Cell and Embryonal; Physiological aspects; Precision oncology; Targeted therapy; Testicular Neoplasms
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2020-0509

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. This article identifies molecular alterations in genes involved in the cyclin activation/sensitizing pathways and reports coexisting resistance and hormone pathway alterations in 190,247 diverse solid tumors that underwent next‐generation