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Novel Therapeutics Target Gene Mutations, Tumor Suppressors

Jonathan S. Batchelor
Published: Tuesday, Aug 02, 2011
David Sidransky, MD

David Sidransky, MD

The genes that populate the squamous cell carcinoma of the head and neck (SCCHN) neighborhood have some new residents in the form of previously unknown genetic methylation patterns and new mutations.

These genetic and epigenetic alterations could prove valuable for diagnosing SCCHN, tracking its progress, and developing targeted therapies, according to David Sidransky, MD, who chaired an educational session at the ASCO meeting on developments in SCCHN.

Sidransky is a professor of oncology, otolaryngology, pathology, genetics, urology, and cellular and molecular medicine at Johns Hopkins University in Baltimore, Maryland. Other speakers at the session were Christine Chung, MD, who outlined new strategies for targeting SCCHN mutations, and Ezra Cohen, MD, who highlighted pivotal trials for disease therapy.

Sidransky’s detailed talk offered 2 major takehome points:

  • At least 2 genes, KIF1A and EDNRB, appear to be highly methylated in SCCHN patients when compared with healthy people who are at risk for SCCHN from smoking and other environmental exposures. The methylation of these genes might aid in disease diagnosis and monitoring.
  • New mutations have cropped up in genes that are not usually associated with SCCHN, including NOTCH1, which is a known genetic mutation in other types of cancer. However, unlike other cancers, NOTCH1 seems to be inactivated in SCCHN.

Table. Top 12 Genes With Mutations in Squamous Cell Carcinoma

Gene
Detection
 
TP53
43%
 
CDKN2a (p14ARF)
39%
 
FGFR3
22%
 
CDKN2A (p16)
18%
 
MET
14%
 
SMAD4
13%
 
HRAS
10%
 
PIK3CA
9%
 
EGFR
3%
 
PTEN
3%
 
KRAS
2%
 
BRAF
1%
 
The mutation data were obtained from the Sanger Institute Catalogue of Somatic Mutations In Cancer Website, http://www.sanger.ac.uk/ cosmic. Bamford et al (2004) The COSMIC (Catalogue of Somatic Mutations in Cancer) database and Website. Br J Cancer. 2004. 91(2):355-358.

Targeting Tumor Suppressors

Tumor suppressors dominate in SCCHN, and the conventional wisdom has been that they are difficult to target with therapeutic agents. But that mindset needs to change, said Chung, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital in Baltimore, Maryland.


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