PMID- 32885893
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20240330
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 26
IP  - 1
DP  - 2021 Jan
TI  - Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging 
      Large-Scale Data to Inform Therapeutic Directions.
PG  - e78-e89
LID - 10.1634/theoncologist.2020-0509 [doi]
AB  - 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 (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.
CI  - (c) 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf 
      of AlphaMed Press.
FAU - Jardim, Denis L
AU  - Jardim DL
AUID- ORCID: 0000-0003-4663-1521
AD  - Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo, Brazil.
FAU - Millis, Sherri Z
AU  - Millis SZ
AD  - Foundation Medicine, Cambridge, Massachusetts, USA.
FAU - Ross, Jeffrey S
AU  - Ross JS
AD  - Foundation Medicine, Cambridge, Massachusetts, USA.
FAU - Woo, Michelle Sue-Ann
AU  - Woo MS
AD  - Foundation Medicine, Cambridge, Massachusetts, USA.
FAU - Ali, Siraj M
AU  - Ali SM
AD  - Foundation Medicine, Cambridge, Massachusetts, USA.
FAU - Kurzrock, Razelle
AU  - Kurzrock R
AD  - Center for Personalized Cancer Therapy and Division of Hematology and Oncology, 
      University of California, San Diego, California, USA.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200915
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
SB  - IM
MH  - Genomics
MH  - *Glioma
MH  - Humans
MH  - Male
MH  - Mutation
MH  - *Neoplasms, Germ Cell and Embryonal
MH  - *Testicular Neoplasms
PMC - PMC7794175
OTO - NOTNLM
OT  - CDK4
OT  - CDK6
OT  - Cancer genome
OT  - Cell cycle
OT  - Molecular genetics
OT  - Precision oncology
OT  - Targeted therapy
COIS- Disclosures of potential conflicts of interest may be found at the end of this 
      article.
EDAT- 2020/09/05 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/01/01
CRDT- 2020/09/05 06:00
PHST- 2020/06/01 00:00 [received]
PHST- 2020/08/14 00:00 [accepted]
PHST- 2020/09/05 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/09/05 06:00 [entrez]
PHST- 2021/01/01 00:00 [pmc-release]
AID - ONCO13504 [pii]
AID - 10.1634/theoncologist.2020-0509 [doi]
PST - ppublish
SO  - Oncologist. 2021 Jan;26(1):e78-e89. doi: 10.1634/theoncologist.2020-0509. Epub 
      2020 Sep 15.