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Sequencing the whole genomes of 110 small-cell lung cancers showed that losing both the p53 and the retinoblastoma genes is not merely common in this cancer, it is obligatory, and that a quarter of tumours have broken a signalling system that would otherwise force them to stop behaving like nerve cells.
The genomes of 110 small-cell lung cancers were sequenced. In nearly all tumours there was biallelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangement. Two tumours with wild-type RB1 showed chromothripsis leading to overexpression of cyclin D1, an alternative route to deregulating the same pathway, so loss of both tumour suppressors is obligatory. Somatic genomic rearrangements of TP73 were discovered that create an oncogenic isoform lacking exons 2 and 3. Kinase gene mutations appeared in rare cases, offering a possible therapeutic opportunity for individual patients. Inactivating mutations in NOTCH family genes were found in 25% of tumours; activating Notch signalling in a mouse model strikingly reduced tumour number and extended survival, and Notch activity abolished neuroendocrine gene expression in small-cell cells.
It settled that small-cell lung cancer has no targetable recurrent driver beyond the two tumour suppressors that are already gone, which is why the field moved to surface antigens and transcriptional states instead of kinase inhibitors.
Shares CREBBP, KMT2D, EP300, Somatic mutations from exome and genome sequencing (WXS, WGS).
Shares Copy number alteration (CNA), NOTCH1, PTEN, RB1.
Shares NOTCH1, Notch signalling, RB1, Driver mutation.
Shares RB1, Lineage plasticity & neuroendocrine transformation, Whole-exome & whole-genome sequencing, TP53.
Shares PTEN, RB1, Nature, p53 / RB / cell-cycle checkpoint.
Shares Copy number alteration (CNA), Chromosomal instability & aneuploidy, Driver mutation, Whole-exome & whole-genome sequencing.
Shares MYCL, Small cell lung cancer (KEGG map), MYC, Lineage plasticity & neuroendocrine transformation.
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), MYC, Chromosomal instability & aneuploidy, Nature.