Temporal Dissection of Tumorigenesis in Primary Cancers

Abstract

Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for two separate cancer types. We detect vast, unreported expansion of simple mutation sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCCs) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Specifically, D469G from EGF‐like repeat domain and R1594Q from the NECD LNR‐C domain significantly reduced ligand‐mediated NOTCH1 activation, whereas P1770S from the RAM domain seems to interfere with Notch signaling at the level of transcription complex assembly. Furthermore, high‐frequent mutation of NOTCH in CSCC was confirmed by exome or targeted sequencing of CSCCs or squamoproliferative lesions 24, 25.…”

Tumour–stroma crosstalk in the development of squamous cell carcinoma

“…Much of the research to assess cross-talk between tumours and their surrounding environment, or stroma, has used cSCC as a model and although skin is distinct in many ways from other tissues such as lung or oesophagus recent deep sequencing of cancer genomes are now suggesting that common initiating mutation events occur in SCC arising across these different tissues implicating disruption of similar pathways (Durinck, Ho et al 2011;Stransky, Egloff et al 2011;Agrawal, Jiao et al 2012;TCGA 2012). It has long been known that TP53 and CDKN2A are frequently mutated in SCC but recent findings of prevalent loss of function mutations in Notch receptors coupled with the described role of Notch signalling in terminal differentiation (Lefort and Dotto 2004) suggests that perturbation of this pathway is a common, early event in SCC development.…”

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

“…34,35 This histological type represents 70% of OVCa. 36 Thus, in principle, the other 30% of histological types and the 4% high-grade serous OVCa left (all of them wild-type TP53) would be suitable for the combined CDDP plus Nut3a treatment.…”