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Global loss manifests itself in partially methylated domains that span up to megabases. However, the distribution of PMDs within and between tumor types of tumor types, as well as their effects on key functional genomic elements including CGIs, is uncertain. We show that loss of methylation in PMDs accounts for a significant portion of the genome and is the leading source of DNA methylation variation. Tumor suppressor genes are largely absent from PMDs, so their effects on tumor suppressor genes are negligible.
Source link: https://www.osti.gov/biblio/1624152
Despite patients with metastatic breast cancer having dismal survival, patterns of genomic evolution between primary and metastatic breast cancer have not been explored in large numbers, despite patients with metastatic breast cancer having dismal survival. On 299 samples from 170 patients with locally relapsed or metastatic breast cancer, We sequenced whole genomes or a panel of 365 genes. Driver mutations that were not present in the primary tumor were seen in the first tumor, derived from a larger range of cancer genes than early responders.
Source link: https://www.osti.gov/biblio/1392804
DCYTB is also a member of a 16-gene iron regulatory gene signature that predicts metastasis-free survival in breast cancer patients. We investigated in detail the prognostic significance and molecular role of DCYTB in breast cancer to help better understand the connection between DCYTB and breast cancer. High DCYTB expression was shown to prolongation in two large independent cohorts, totaling 1610 patients as well as the Gene expression-based Outcome for Breast Cancer Online cohort. Because SPIA pathway analysis of patient microarray results revealed an association between DCYTB and the focal adhesion pathway, we investigated the role of DCYTB on FAK activation in breast cancer cells. Rather, DCYTB may delay tumor formation by reducing FAK production, a protein that plays a key role in tumor cell adhesion and metastasis.
Source link: https://www.osti.gov/biblio/1626928
The mutagenized landscape of cancer genomes is a result of chemical rearrangements. We systematically interrogated rearrangements in 560 breast cancers using a piecewise constant fitting method. These hotspots may be points of selective vulnerability to double-strand-break attack due to high transcriptional saturation, or, by increasing copy number, could be sites of secondary selective pressure. In addition, transcriptional consequences varied from strong individual oncogene to weak but quantifiable multigene expression effects.
Source link: https://www.osti.gov/biblio/1341860
There are well-known links of ionizing radiation for female breast cancer, as well as emerging evidence for male breast cancer. Female breast cancer in the United Kingdom is one of those cancers eligible for state insurance, and an extension to include male breast cancer is now available in the United Kingdom. Breast cancer incidence and mortality among the Japanese atomic-bomb survivors were analyzed using relative and absolute risk models by Poisson regression. As a result, we discovered a significant dose-related excess risk for male breast cancer incidence and mortality. According to prevalence and mortality estimates, there are approximate 15-fold and 5-fold elevations of relative risk for males relative to female breast cancer incidence relative to male breast cancer incidence, respectively. The likelihood of male breast cancer following radiation exposure is more than four times higher than that of several other malignancies.
Source link: https://www.osti.gov/biblio/1356160
To investigate ROCK function, we used biologically viable 3D cultures of nonmalignant and cancer cells in gels made of laminin-rich extracellular matrix. Whereas expression levels of ROCK1 and ROCK2 were higher in cancer cells compared to nonmalignant cells, this was not present in 2D cultures. ROCK inhibition also reduced EGFR and Integrin1 levels, which in turn reduced Akt, MAPK, and FAK activation, as well as GLUT3 and LDHA levels. High amounts of ROCK were present in a triple negative breast cancer cell line, but not so sensitive to ROCK inhibitors.
Source link: https://www.osti.gov/biblio/1627992
To advance knowledge of the driver mutations that conferring clonal advantage and the mutational pathways that produce somatic mutations, we examined whole-genome sequences of 560 breast cancers here. We discovered that 93 protein-coding cancer genes contained probable driver mutations. Some non-coding areas had higher mutation rates, but most had identifiable structural characteristics that could have raised mutation rates and do not contain driver mutations. This review of breast cancer's somatic genetics provides an extensive view of the somatic genetic basis.
Source link: https://www.osti.gov/biblio/1255873
Human cancer genetic variations show variations in genomic distribution that correlate with features of genome organization and function. Here we show that each of 12 base substitution, 2 deletion/deletion, and 6 rearrangement mutational signatures present in breast tissue demonstrate distinct links with genomic functions related to transcription, DNA replication, and chromatin organization, with somatic mutation catalogs from 560 breast cancer whole-genome sequences.
Source link: https://www.osti.gov/biblio/1256099
Sequencing cancer genomes can facilitate the development of therapeutics tailored to a particular patient's tumor's genetic abnormalities. We used whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors in order to determine the subclinal region of primary breast cancer. Some tumors develop early in some tumors and later in others, according to point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2, and MYC, which appear early in some tumors and late in others. These results show that including studies of subclinal morphology and tumor evolution in clinical trials of primary breast cancer are vital.
Source link: https://www.osti.gov/biblio/1236604
Are there some unique MRN variants intermediate-risk breast cancer susceptibility alleles, and if so, do the MRN genes follow a BRCA1/BRCA2 pattern, wherein most susceptibility alleles are protein-truncation variants, or do they follow an ATM/CHEK2 scheme wherein half or more of the susceptibility alleles are missense substitutes? Methods: We mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls in 1,313 early-onset breast cancer cases and 1,123 population controls using high-resolution melt curve modeling and Sanger sequencing. We found convincing evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes, with variants including allele frequencies of 0. 1% and combining protein-truncating variants, most likely spliceogenic variants, and important functional domain rare missense substitutes.
Source link: https://www.osti.gov/biblio/1626700
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