title: 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 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) 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.
authors: Life Sciences Division, Lawrence Berkeley National Laboratories, USA.
authors: Steffen
authors: S
authors: Durinck
authors: Christine
authors: C
authors: Ho
authors: Nicholas J
authors: NJ
authors: Wang
authors: Wilson
authors: W
authors: Liao
authors: Lakshmi R
authors: LR
authors: Jakkula
authors: Eric A
authors: EA
authors: Collisson
authors: Jennifer
authors: J
authors: Pons
authors: Sai-Wing
authors: SW
authors: Chan
authors: Ernest T
authors: ET
authors: Lam
authors: Catherine
authors: C
authors: Chu
authors: Kyunghee
authors: K
authors: Park
authors: Sung-woo
authors: SW
authors: Hong
authors: Joe S
authors: JS
authors: Hur
authors: Nam
authors: N
authors: Huh
authors: Isaac M
authors: IM
authors: Neuhaus
authors: Siegrid S
authors: SS
authors: Yu
authors: Roy C
authors: RC
authors: Grekin
authors: Theodora M
authors: TM
authors: Mauro
authors: James E
authors: JE
authors: Cleaver
authors: Pui-Yan
authors: PY
authors: Kwok
authors: Philip E
authors: PE
authors: LeBoit
authors: Gad
authors: G
authors: Getz
authors: Kristian
authors: K
authors: Cibulskis
authors: Jon C
authors: JC
authors: Aster
authors: Haiyan
authors: H
authors: Huang
authors: Elizabeth
authors: E
authors: Purdom
authors: Jian
authors: J
authors: Li
authors: Lars
authors: L
authors: Bolund
authors: Sarah T
authors: ST
authors: Arron
authors: Joe W
authors: JW
authors: Gray
authors: Paul T
authors: PT
authors: Spellman
authors: Raymond J
authors: RJ
authors: Cho
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D009154:Mutation; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53