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This Week in NEJM: Jan 19, 2012


In NEJM this week, an international team of researchers reports a study of RAS mutations in patients with cutaneous squamous cell carcinoma who were treated with BRAF inhibitors. The team analyzed oncogenic mutations in the lesions of 21 patients treated with BRAF inhibitor vemurafenib. Out of the 21, 13 had RAS mutations, the team found, as did eight out of 14 samples in a validation set. The most prevalent was HRAS Q61L, the team writes, adding that "increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription." In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the researchers found that a concomitant treatment with a MEK inhibitor blocked the growth of lesions harboring HRAs mutations.

In a related editorial in NEJM this week, the Wistar Institute's Ashani Weeraratna says that while BRAF inhibitors have helped many melanoma patients, the "paradox" of these drugs is the development of cutaneous squamous-cell carcinomas and keratoacanthomas that occur in response to treatment. Recent data reveals the mutations behind these secondary cancers have certain implications for how oncologists use BRAF inhibitors, Weeraratna says. For one, all patients being given these drugs should also be tested for RAS mutations. "Second," she adds, "these data underscore how critical it is to understand the mechanism of action of targeted therapies, which not only will alert us to potential clinical toxic effects (e.g., squamous-cell carcinomas), but can help us rationally design alternative or complementary therapies (e.g., MEK inhibition)."

The Scan

Study Examines Insights Gained by Adjunct Trio RNA Sequencing in Complex Pediatric Disease Cases

Researchers in AJHG explore the diagnostic utility of adding parent-child RNA-seq to genome sequencing in dozens of families with complex, undiagnosed genetic disease.

Clinical Genomic Lab Survey Looks at Workforce Needs

Investigators use a survey approach in Genetics in Medicine Open to assess technologist applications, retention, and workforce gaps at molecular genetics and clinical cytogenetics labs in the US.

Study Considers Gene Regulatory Features Available by Sequence-Based Modeling

Investigators in Genome Biology set sequence-based models against observational and perturbation assay data, finding distal enhancer models lag behind promoter predictions.

Genetic Testing Approach Explores Origins of Blastocyst Aneuploidy

Investigators in AJHG distinguish between aneuploidy events related to meiotic missegregation in haploid cells and those involving post-zygotic mitotic errors and mosaicism.