Histone-Modifying Gene Mutations a 'Major Feature' in Small-Cell Lung Cancer

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(ChemotherapyAdvisor) –  Histone-modifying gene mutations are strongly associated with small-cell lung cancer (SCLC), a very aggressive type of lung tumor, according to a pioneering genome and transcriptome study of mutation rates in small-cell lung tumors, published in Nature Genetics.

“Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background,” reported senior author Roman K. Thomas, MD, Department of Translational Genomics, University of Cologne, Germany, and more than 50 other coauthors.

The team sequenced two entire SCLC genomes, 29 exomes (representing gene-encoding regions), and 15 RNA transcriptomes. The sequencing revealed an “extremely high mutation rate” of 7.4± 1 protein-changing mutations per million base pairs, they reported.

Subsequent analyses revealed strong evidence for “pathogenetically-relevant” inactivations of TP53 and RB1, and recurrent mutations in several histone-modifier genes (CREBBP, EP300 and MLL) and other genes (PTEN, SLIT2, and EPHA7). The tyrosine kinase gene FGFR1 was also focally amplified.

“Beyond universal losses of TP53 and RB1 and amplifications of MYCL1, MYCN and MYC, we present PTEN mutations and FGFR1 amplifications as potentially therapeutically-tractable genome alterations,” the authors wrote.

The histone-modifying gene mutations were the second most-frequently mutated class of genes in SCLC, beyind TP53 and RB1 mutations, they reported.  PTEN mutations were seen in 3 of 29 cases; these mutations are associated with aberrant phosphatase activity. MLL mutations are also seen in acute leukemias, the authors noted.

“(O)ur study represents a considerable extension of the current molecular concept of SCLC and, more broadly, provides an example of how integrative computational genome analyses can provide functionally tractable information in the context of a highly-mutation cancer genome,” they concluded.

SCLC represents 15% of all lung cancer cases, and is most frequently seen in heavy tobacco smokers. It is associated with aggressive tumor growth and early metastasis and death. SCLC genomics have been little researched before the new study, largely because tumors are “rarely treated by surgery, resulting in a lack of suitable fresh-frozen tumor specimens,” the authors concluded.

Abstract

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