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

Our plain-English summary of Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions, by D.L. Jardim, S.Z. Millis, J.S. Ross, et al (The Oncologist, 2021).

The study

• Authors: D.L. Jardim, S.Z. Millis, J.S. Ross, M.S. Woo, S.M. Ali, R. Kurzrock
• Journal: The Oncologist
• Published: 2021;26(1):e78-e89
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

In plain English

This study analyzed genetic test results from 190,247 solid tumors. Physicians worldwide sent the samples to one commercial laboratory, which tested 315 cancer-related genes. The authors looked for changes in genes of the "cyclin pathway", which helps control cell division. The study did not look at asbestos or any other exposure. Mesothelioma was one of 33 disease types examined, and the article does not say whether these cases were pleural or peritoneal. Overall, 24% of tumors had at least one change in eight cyclin genes the authors classed as activating or sensitizing. Brain tumors (47.1%), esophageal cancers (40.3%), mesotheliomas (37.9%) and bladder cancers (37.9%) were among the most often affected. Changes in two genes linked to drug resistance, RB1 and CCNE1, were found in 7.2% and 3.6% of samples. In most disease types, including mesothelioma, sensitizing and resistance changes were less likely to occur together than separately. The authors concluded that patterns differed between and within tumor types, suggesting a need for individual genetic testing. They noted the study had no clinical information about patient outcomes or treatment response.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of tumor genetic sequencing results (comprehensive genomic profiling) from a commercial laboratory; no clinical outcome data
• Who was studied: 190,247 solid tumor samples submitted by physicians worldwide to Foundation Medicine (Cambridge, Massachusetts), grouped into 33 disease types and 17 histologies. Mesothelioma was one disease type (1,004 samples in the co-occurrence table). Collection dates are not stated.
• Exposure: No asbestos or environmental exposure was studied. The study examined genetic alterations in eight cyclin activating/sensitizing genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B loss, CDKN2A loss, SMARCB1), two resistance genes (RB1, CCNE1), related genes (SMAD3, CDKN1A, CDKN1B, CDKN2C) and hormone receptor genes (ESR1, AR).
• Main results:
  • Across all 190,247 tumors, 24% had an alteration in at least one cyclin activating/sensitizing gene.
  • Across all tumors, the most frequent alterations were CDKN2A loss (13.9%), CDKN2B loss (12.5%) and CCND1 amplification (4.8%).
  • By disease type, the highest rates of any cyclin activating/sensitizing alteration were in brain tumors (47.1%), esophageal cancer (40.3%), mesothelioma (37.9%), bladder cancer (37.9%) and primary bone cancers (35.7%).
  • Across all tumors, alterations in the resistance genes RB1 and CCNE1 were found in 7.2% and 3.6% of samples, respectively.
  • For all tumors combined, sensitizing and resistance alterations were less likely to occur together than separately (odds ratio 0.35). The exceptions were colorectal (OR 1.53), cervical (OR 1.29) and small intestine (OR 1.28) cancers.
  • Among the 1,004 mesotheliomas in the co-occurrence table, 378 had sensitizing alterations only, 21 had resistance alterations only, 5 had both and 600 had neither. The odds ratios were 0.50 and 0.39.
  • Hormone receptor alterations occurred together with cyclin activating/sensitizing alterations more often than expected in three cancers: AR in prostate cancer (OR 1.79), ESR1 in breast cancer (OR 1.63 in the results text) and ESR1/AR in cervical cancer (OR 4.08, p = .04).
  • SMARCB1 alterations were rare overall (0.7%) but frequent in some rare tumors, including kidney rhabdoid tumor (90%) and brain rhabdoid tumor (88.4%).
• The authors' conclusion: The authors concluded that cyclin pathway alteration patterns differed between tumor types and between patients within a cancer type. In their view, this suggests a need for individual genetic profiling (NGS) if these alterations are to be used for treatment.
• Limitations the authors state:
  • The study had no clinical information, so links between the genetic alterations and prognosis or treatment response could not be studied.
  • The test used could not detect epigenetic changes or noncoding genetic alterations that may also affect the cyclin pathway.

Topics

Medical terms in this study, explained in our Lexicon: CDKN2A, Mesothelioma, Sarcoma, Rhabdoid, Odds Ratio, Histology, Targeted Therapy.

Related studies

• Rare tumors of the testis and mesothelial proliferation in the tunica vaginalis — M. Colecchia, G. Mikuz, et al. (2012)
• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)
• Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas — J.M. Sands, T. Nguyen, et al. (2020)
• INTEROCC case-control study: lack of association between glioma tumors and occupational exposure to selected combustion products, dusts and other chemical agents — A. Lacourt, E. Cardis, et al. (2013)
• Putative Malignant Pleural Mesothelioma in situ (MPMIS) with Sequential Acquisition of Genomic Alterations on Fluorescence in situ Hybridization (FISH) Examination — S. Haefliger, S. Savice Prince, et al. (2021)
• Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma — J. Creaney, A.M. Patch, et al. (2022)

Browse more research in The Oncologist, or return to medical research.