Editors' ChoiceCancer

A Cut Deeper in the Lung and Colorectal Cancer Genome

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Science Translational Medicine  22 Feb 2012:
Vol. 4, Issue 122, pp. 122ec30
DOI: 10.1126/scitranslmed.3003869

With the continuing advances in modern technology, many objects and concepts have become obsolete: When was the last telegram sent? Modern genetics has provided not only a deeper and better understanding of pathophysiology of many diseases, but also has changed the definitions and classifications of disorders. For example, many cancers that were previously classified by anatomical location now are differentiated by genetic signatures—with specific prognoses and targeted therapies. Lipson et al. now extend these advances in lung and colorectal cancers; they identify new gene fusions that may be able to be targeted with multikinase inhibitors already in clinical use.

The authors sequenced genomic DNA from both colorectal cancer and non–small cell lung cancer (NSCLC) samples, targeting 145 genes previously associated with diverse cancers. They identified genetic alterations in most, but not all, of the samples, with some genes being altered in multiple tumors. In addition to mutations known to associate with these particular cancer types, Lipson et al. also found some surprising results. A JAK2 (Janus kinase 2) V617F mutation frequently reported in myeloproliferative neoplasms but not solid tumors was detected in three subjects with NSCLC.

The researchers also discovered two previously unidentified fusion genes: KIF5B-RET (kinesin family member 5B - Rearranged during Transfection) was found in 1 to 2% of never or limited former smokers with NSCLCs, and C2orf44-ALK (chromosome 2 open reading frame 44 - analplastic lymphoma kinase) was detected in one colorectal specimen. The lack of known oncogenic mutations in individuals positive for the KIF5B-RET fusion suggests that the RET fusion might be a driving oncogenic event.

The findings by Lipson et al. suggest that ALK, RET, and JAK2 inhibitors, some of which are already available in the clinic for other disorders, may provide efficacious targeted therapeutic options for the small subpopulation of individuals with colorectal cancers and NSCLCs that harbor these genetic alterations. Although these hypotheses remain to be tested in prospective well-designed, well-conducted clinical trials, this deeper cut in the cancer genome is providing more ammunition for an intelligent fight against cancer.

D. Lipson et al., Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat. Med., 12 February 2012 (10.1038/nm.2673). [Abstract]

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