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Genomics In The Journals: Aug 4, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A pair of studies in Science Express are providing clues about the sorts of mutations that contribute to head and neck cancer.

Broad Institute researcher Levi Garraway and University of Pittsburgh researcher Jennifer Grandis led a team that did whole-exome sequencing on 74 head and neck squamous cell carcinoma tumors and on matched normal samples for each. They found mutations in several known head and neck cancer genes, including TP53, CDKN2A, PTEN, PIK3CA, and HRAS, as well as previously undetected mutations in several other genes. In particular, the team reported that nearly one-third of the tumors harbored mutations in genes contributing to the process of squamous differentiation — among them: NOTCH1, IRF6, and TP63.

Meanwhile, a team led by several investigators at Johns Hopkins and the MD Anderson Cancer Center used exome sequencing and copy number analyses to assess 32 head and neck squamous cell carcinomas before doing follow-up analyses on dozens of other tumor samples. When they compared mutation patterns in cancers from individuals with or without a history of smoking, the researchers saw about twice as many mutations in the smoker group. On the other hand, tumors corresponding to human papilloma virus infection had far fewer mutations than the HPV-negative tumors.

Along with mutations in known head and neck cancer contributors, the team found that the HNSCC tumors tended to have recurrent mutations in FBXW7 and NOTCH1. Though NOTCH1 is thought to be an oncogene in some cancer types, their results led them to speculate that it may act as a tumor suppressor in head and neck cancer.

"Our study suggests that a gene's role can depend on the tumor type," co-corresponding author Kenneth Kinzler, co-director of the Johns Hopkins Ludwig Center, said in a statement. "In some cases, a gene can act as a growth promoter in cancer, and in other cases, such as head and neck cancer, the same gene behaves as a growth suppressor."

An American and Austrian research group says the Brd4 gene, which codes for a protein that binds acetylated histones, may prove useful as a drug target in acute myeloid leukemia. The team found Brd4 via an RNA interference screen in a mouse model of AML, using a library of custom small hairpin RNAs that targeted hundreds of chromatin regulatory genes. The absence of Brd4 curbed AML progression, the team reported in Nature, spurring efforts to further test and develop a small molecule inhibitor of the gene known as JQ1.

"The drug candidate not only displays remarkable anti-leukemia activity in aggressive disease models and against cells derived from patients with diverse, genetic subtypes of AML, but is also minimally toxic to non-cancerous cells," senior author Chris Vakoc, a researcher at Cold Spring Harbor Laboratory, said in a statement. "The drug is currently being developed for therapeutic use for cancer patients by Tensha Therapeutics and is expected to enter clinical trials within two years."

Researchers from the US and Brazil used exome sequencing to find genetic glitches behind a type of brain cancer called oligodendroglioma — work that they outline in a study in the early, online edition of Science. The team sequenced the coding sequences from seven oligodendroglioma tumors with the Illumina HiSeq platform. Analyses of these exomes turned up translocations involving chromosomes 1 and 19, which were known to be common in oligodendrogliomas. But the investigators also found recurrent mutations affecting two genes on these chromosomes: the chromosome 19 gene CIC and the chromosome 1 gene FUBP1, both involved in cell signaling. When they screened dozens more oligodendroglioma samples, the researchers found CIC mutations in more than 44 percent of tumors. FUBP1 was mutated in about 11 percent.

"We can focus now on when these mutations develop during tumor formation, whether they can guide prognosis, and how they might form targets for therapy," co-first author Chetan Bettegowda, chief resident in Johns Hopkins' neurosurgery department, said in a statement.

An American Journal of Human Genetics study shows that mutations in a diminutive isoform of the gene SMARCAD1 that's only found in the skin are associated with a rare genetic condition known as adermatoglyphia, characterized by a lack of fingerprints and hands that are less sweaty than usual. Israeli and Swiss researchers narrowed in on the gene — which seems to influence the expression of several other genes — through linkage and haplotype analyses of nine affected and seven unaffected members of a Swiss family.

"Taken together, our findings implicate a skin-specific version of SMARCAD1 in the regulation of fingerprint development," senior author Eli Sprecher, a molecular genetics and biochemistry researcher at Tel-Aviv University, said in a statement. "Further, as abnormal fingerprints are known to sometimes herald severe disorders, our finding may also impact the understanding of additional diseases affecting not only the skin."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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