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Sequencing the DNA and the RNA of more than 70 colon tumours turned up a new way of switching on the growth signal that drives the disease: two genes fused so that an amplifier of the WNT pathway is overproduced, in tumours whose usual brake gene is intact.
More than 70 pairs of primary human colon tumours and matched normal tissue were analysed by exome, transcriptome and copy-number sequencing, identifying 36,303 protein-altering somatic changes. New recurrent mutations were found in the WNT pathway gene TCF7L2, in chromatin-remodelling genes including TET2 and TET3, and in receptor tyrosine kinases including ERBB3; 23 significantly mutated genes were identified, including ATM. Copy-number and RNA sequencing found amplification and corresponding overexpression of IGF2. Recurrent gene fusions involving RSPO2 and RSPO3 together occurred in 10% of the tumours, were mutually exclusive with APC mutation, and potentiated WNT signalling in functional assays.
Deposited as coadread_genentech on cBioPortal (72 sequenced tumours).
It gave the WNT pathway a second, druggable entry point: RSPO fusion tumours still need the upstream receptor complex, so they are the population porcupine and RSPO3 inhibitors are being tested in.
Shares TCF7L2, APC, Wnt / β-catenin, Nature.
Shares APC, Wnt / β-catenin, Nature, Whole-exome & whole-genome sequencing.
Shares APC, Nature, Whole-exome & whole-genome sequencing, Colorectal cancer.
Shares APC, Wnt / β-catenin, Colorectal cancer.
Shares APC, Nature, Whole-exome & whole-genome sequencing, Colorectal cancer.
Shares Receptor tyrosine kinase activation, HER2, Colorectal cancer.
Shares RNA sequencing & expression profiling, Whole-exome & whole-genome sequencing.