Editors' ChoiceCancer

Small cell lung cancer in profile

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Science Translational Medicine  05 Aug 2015:
Vol. 7, Issue 299, pp. 299ec135
DOI: 10.1126/scitranslmed.aac9322

Small cell lung cancer (SCLC) is one of the most aggressive human cancers and affects over 30,000 patients a year in the United States alone. Standard treatments have not changed in decades, and the 5-year survival rate is less than 7%. One of the major challenges to studying SCLC tumorigenesis is the lack of tumor tissue for clinical and molecular studies. Because the disease is so aggressive, most patients are started on treatment right away after the diagnosis is confirmed with minimal tissue.

George et al. report the sequencing of fresh-frozen tumor specimens obtained from 110 patients diagnosed with SCLC. Consistent with the high genome-wide burden of mutations observed in smoking-related cancers, this study found extremely high mutation rates in the SCLC genome. Despite this, very few of the tumors had mutations in known oncogenic drivers that usually respond to targeted therapies. Biallelic inactivation of TP53 and RB1 was observed in nearly all samples and included some previously unidentified complex genomic rearrangements, suggesting an even broader involvement of P53 and RB family members in SCLC tumorigenesis than previously thought. In the only two cases in which TP53 and RB1 were not altered, a pattern of massive gene rearrangement between chromosomes 3 and 11 was observed. This rearrangement resulted in overexpression of cyclin D1, possibly representing an alternative mechanism of RB1 deregulation in these tumors. Alterations in NOTCH family members were seen in a quarter of the samples. Conditional overexpression of an activated form of NOTCH1 or NOTCH2 in a mouse model resulted in a marked reduction in the number of tumors as well as increased survival, supporting the role of NOTCH as a tumor suppressor in SCLC.

The tumors were derived largely from patients with early-stage disease; therefore, further studies will be needed to clarify how the disease might differ in late-stage patients and at relapse. Nevertheless, this study provides the most comprehensive view to date into the genomic profile of SCLC and uncovers several key biological processes in this highly lethal form of cancer.

J. George et al., Comprehensive genomic profiles of small cell lung cancer. Nature 10.1038/nature14664 (2015). [Abstract]

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