Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 12;4(1):567.
doi: 10.1038/s42003-021-02020-5.

The oncological relevance of fragile sites in cancer

Benjamin S Simpson  1 , Hayley Pye  1 , Hayley C Whitaker  2
Affiliations
Review

The oncological relevance of fragile sites in cancer

Benjamin S Simpson et al. Commun Biol. .

Abstract

Recent developments in sequencing the cancer genome have provided the first in-depth mapping of structural variants (SV) across 38 tumour types. Sixteen signatures of structural variants have been proposed which broadly characterise the variation seen across cancer types. One signature shows increased duplications and deletions at fragile sites, with little association with the typical DNA repair defects. We discuss how, for many of these fragile sites, the clinical impacts are yet to be explored. One example is NAALADL2, one of the most frequently altered fragile sites in the cancer genome. The copy-number variations (CNVs) which occur at fragile sites, such as NAALADL2, may span many genes without typical DNA repair defects and could have a large impact on cell signalling.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Overview of evidence surrounding the fragile site NAALADL2’s association with aggressive PCa.
a The Frequency of NAALADL2 amplifications increases with Gleason grade, tumour stage and local metastasis in PCa. b Upper: Location of NAALADL2 on Chromosome 3; The lightning symbol indicates the location of the fragile site. The red box indicates the extent of the region that can co-amplify with the NAALADL2 genomic region surrounding 3q26.31, which is rich in oncogenes. Lower: pictograph displaying nearby oncogenes co-amplified with NAALADL2 in PCa. The x-axis shows the genomic location of genes within the amplicon, the y-axis represents significant co-occurrence (−Log10 p-value). c Increased copy number results in increased transcription of oncogenes through the ‘gene dosage’ effect as well as downstream activation of other oncogenes. The diagram shows tumour cells replicating following a number of pro-proliferative mRNA signalling pathways becoming activated.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schwartz M, Zlotorynski E, Kerem B. The molecular basis of common and rare fragile sites. Cancer Lett. 2006;232:13–26. doi: 10.1016/j.canlet.2005.07.039. - DOI - PubMed
    1. Li Y, et al. Patterns of somatic structural variation in human cancer genomes. Nat. 2020;578:112–121. doi: 10.1038/s41586-019-1913-9. - DOI - PMC - PubMed
    1. Smith DI, Zhu Y, McAvoy S, Kuhn R. Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett. 2006;232:48–57. doi: 10.1016/j.canlet.2005.06.049. - DOI - PubMed
    1. Wilson TE, et al. Large transcription units unify copy number variants and common fragile sites arising under replication stress. Genome Res. 2015;25:189–200. doi: 10.1101/gr.177121.114. - DOI - PMC - PubMed
    1. Aguilera A, Garcia-Muse T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell. 2012;46:115–124. doi: 10.1016/j.molcel.2012.04.009. - DOI - PubMed

Publication types

Substances

LinkOut - more resources

-