Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma - 30 whole exomes

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signaling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development. These findings indicate that LGR5+ve stem cells can act as cells of origin for cSCC and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signaling, are driving events of skin tumorigenesis.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 2 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001002253	Thirty cutaneous SCC WES tumour samples with matched normal include 20 samples from South et al. JID and 10 new samples. These 30 samples has been used to support the findings in the TGFb Nature Communications paper (DOI: 10.1038/ncomms12493). They are also a part of the ongoing study of cSCC genomic landscape of 40 cSCC samples in total.	Illumina HiSeq 2500	60
EGAD00001003555	40 paired normal and tumour whole-exome sequencing samples was used to investigate the genomic landscape of cutaneous squamous cell carcinoma	Illumina HiSeq 2500	80

Publications	Citations
Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Cammareri P, Rose AM, Vincent DF, Wang J, Nagano A, Libertini S, Ridgway RA, Athineos D, Coates PJ, McHugh A, Pourreyron C, Dayal JH, Larsson J, Weidlich S, Spender LC, Sapkota GP, Purdie KJ, Proby CM, Harwood CA, Leigh IM, Clevers H, Barker N, Karlsson S, Pritchard C, Marais R, Chelala C, South AP, Sansom OJ, Inman GJ. Nat Commun 7: 2016 12493	58
The landscape of driver mutations in cutaneous squamous cell carcinoma. Chang D, Shain AH. NPJ Genom Med 6: 2021 61	43

Publications

Citations

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma.
Cammareri P, Rose AM, Vincent DF, Wang J, Nagano A, Libertini S, Ridgway RA, Athineos D, Coates PJ, McHugh A, Pourreyron C, Dayal JH, Larsson J, Weidlich S, Spender LC, Sapkota GP, Purdie KJ, Proby CM, Harwood CA, Leigh IM, Clevers H, Barker N, Karlsson S, Pritchard C, Marais R, Chelala C, South AP, Sansom OJ, Inman GJ. Nat Commun 7: 2016 12493

The landscape of driver mutations in cutaneous squamous cell carcinoma.
Chang D, Shain AH. NPJ Genom Med 6: 2021 61