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Genomic Profiling of SCLC Highlights Importance of Inactivated Genes in Disease Development

NEW YORK (GenomeWeb) – Nearly every small cell lung cancer harbors inactivated TP53 and RB1 genes, according to a comprehensive genomic analysis of the disease.

An international team of researchers led by Roman Thomas at the University of Cologne sequenced 110 small cell lung cancer samples to find that all but two of them had inactivated TP53 and RB1 genes, as they reported today in Nature. Their survey of the genomic landscape of the disease also found that quite a few tumors had genomic rearrangements or mutations involving the TP73 gene as well as kinase gene mutations and inactivating mutations in Notch family genes.

"In summary, we have provided the first, to our knowledge, comprehensive genomic analysis of SCLC, implicating several previously unknown genes and biological processes in the pathogenesis of this disease as possible targets for more efficacious targeted therapeutic intervention against this deadly cancer," Thomas and his colleagues wrote in their paper.

The researchers amassed 152 fresh-frozen tumor and matched normal samples for sequencing, though they excluded 42 cases due to low or poor quality DNA. They also generated transcriptome profiles for 71 of the 110 samples sequenced, and analyzed 103 of the 110 samples along with a further 39 samples using SNP arrays.

Overall, the researchers noted an extremely high mutation rate in SCLC — an estimated 8.62 nonsynonymous mutations per million base pairs — and a preponderance of transversions that are a hallmark of heavy smoking.

By applying a number of analytical filters, the researchers homed in on mutations that seemed relevant to SCLC biology even in this context of high background mutations.

All but two of the 110 tumors the researchers analyzed had inactivated TP53 and RB1 genes, a much higher percentage than what has been previously reported, they noted.

In addition, all or close to all, of these 108 tumors had bi-allelic losses of TP53 and RB1. The mutations typically affected the DNA binding domain of TP53 and exon-intron junctions in RB1, which lead to protein damaging splice events.

The two tumors that lacked these mutations were marked by chromothripsis that had massive rearrangements involving chromosome 3 and chromosome 11 that resulted in CCND1 overexpression. As cyclin D1 negatively regulates Rb family proteins, this suggested to the researchers that the effects of chromothripsis compensated for the presence of wild-type RB1 in the tumors.

This, the researchers added, indicates that TP53 and RB1 seem to follow the classical two-hit paradigm of oncogenesis in SCLC, and that the loss of function of both TP53 and RB1 is needed for SCLC pathogenesis.

In addition, about 13 percent of the tumors Thomas and his colleagues analyzed had genomic breakpoints or mutations affecting the TP73 locus. TP73, the researchers noted, is a TP53 homolog. For example, they uncovered rearrangements that created N-terminally truncated transcript variants like p73Δex2, p73Δex2/3, and p73Δex10, findings they confirmed in their transcriptome data.

In general, p73 with a shortened N-terminus has a dominant negative function on wild-type p73 and p53, the researchers said. They further noted that therapeutics have recently been identified that restrict p73-dependent tumor growth in vivo.

Further, more than three-quarters of the tumors the researchers examined had high expression levels of the neuroendocrine markers CHGA and GRP, and of DLK1, a non-canonical inhibitor of Notch signaling, and of ASCL1, an oncogene whose expression is inhibited by active Notch signaling.

This, they noted, suggests low Notch pathway activity in many SCLC tumors.

Mouse models of the disease with knocked-out Notch pathways developed more tumors, the researchers reported, adding that ectopic expression of a Notch expression plasmid inhibited the growth of murine and human SCLC cell lines.

This, they noted, could provide a link between Notch and the neuroendocrine phenotype in SCLC.

A small portion of tumors also harbored kinase mutations, such as in BRAF or KIT, indicating that some SCLC patients may benefit from genotyping and targeted kinase inhibitor therapy.

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