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Oncogenic mutations select and sculpt conditional cooperative networks in breast cancer

ABSTRACT: Many cancers show recurrent copy number aberrations (CNA) affecting large regions of the genome. To identify genes responsible for this we performed Sleeping Beauty (SB) screens in eight different mouse models of breast cancer. Transposon insertion site analysis identified ~1000 cancer genes, most of which are driver- and/or histotype-specific and appear to have sustained loss-of-function insertions in a single allele. This list greatly exceeds the number identified through searches for recurrent focal mutations. Many SB-targeted genes were identified that function on the same driver-specific pathway responsible for tumor initiation. Some pairs of genes were co-targeted in tumors, and when tested, two such pairs of hemizygous loss-of-function mutations showed significant cooperative interaction with respect to mammary tumor induction. Thus, oncogenic mutations, including haploinsufficient tumor suppressors located in common regions of CNA, form conditional cooperative networks that select and sculpt “just enough and just right” levels of oncogenic signaling in transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE143503 | GEO | 2021/06/29

REPOSITORIES: GEO

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Project description:Somatic mosaicism for DNA copy number alterations (SMC-CNA) is defined as gain or loss of chromosomal segments in mitotic cells within a single organism. As cells harboring SMC-CNA have the potential to undergo clonal expansion, SMC-CNA may be present in a substantial portion of cells in differentiated human tissues and may contribute to the predisposition of these cells to genetic disease including cancer. We characterized gross genomic alterations (>500 kbp) in uninvolved glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array based comparative genomic hybridization experiments showed 10% (6/59) of patients harbored 1 - 359 large SMC-CNA (mean: 1328 kbp; median: 961 kbp) in uninvolved glandular tissue. SMC-CNA were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-can, indicating genomic destabilization. Therefore, we hypothesized that the observed genomic destabilization is predetermined by mutations in genes related to maintenance of genomic integrity. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations in the following genes: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro) and TP53 (p.Arg306*). We demonstrated that gross SMC-CNA may be present in a substantial portion of glandular tissue cells, which are distant from that of the tumor cells, and may co-occur with point mutations in crucial cancer predisposing or somatic driver genes. Taken together, this highlights temporal and spatial neoplastic potential of uninvolved glandular tissue from breast cancer patients. Characterization of gross genomic alterations (>500 kbp) in uninvolved glandular tissue from 59 breast cancer patients and in the matched samples of primary tumors and lymph node metastases. Corresponding peripheral blood lekocyte DNA, a pool of female DNA (Promega), or uninvolved glandular tissue DNA was used as reference. No biological replicates are included.

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Oncogenic mutations select and sculpt conditional cooperative networks in breast cancer

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