Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In order to address the extent to which chromosomal structural rearrangement breakpoints correlate with recurrent DNA double-strand breaks (DSBs), we simultaneously mapped chromosome structural variation breakpoints (using whole-genome DNA-seq) and spontaneous DSB formation (using Break-seq) in the estrogen receptor (ER)-positive breast cancer cell line MCF-7 and a non-cancer control breast epithelium cell line MCF-10A. We identified concurrent DSBs and structural variation breakpoints almost exclusively in the pericentromeric region of chromosome 16q in MCF-7 cells. We fine-tuned the identification of copy number variation breakpoints on 16q. In addition, we detected recurrent DSBs that occurred in both MCF-7 and MCF-10A. We propose a model for DSB-driven chromosome rearrangements that lead to the translocation of 16q, likely with 10q, and the eventual 16q loss that does not involve the pericentromere of 16q. We present evidence from RNA-seq data that select genes, including SHCBP1, ORC6, and MYLK3, which are immediately downstream from the 16q pericentromere, show heightened expression in MCF-7 cell line compared to the control. Data published by The Cancer Genome Atl Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ). Abstract Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In addition, we detected recurrent DSBs that occurred in both MCF-7 and MCF-10A. We propose a model for DSB-driven chromosome rearrangements that lead to the translocation of 16q, likely with 10q, and the eventual 16q loss that does not involve the pericentromere of 16q. We present evidence from RNA-seq data that select genes, including SHCBP1, ORC6, and MYLK3, which are immediately downstream from the 16q pericentromere, show heightened expression in MCF-7 cell line compared to the control. Data published by The Cancer Genome Atlas show that all three genes have increased expression in breast tumor samples. We posit that simultaneous mapping of DSBs and chromosome translocation breakpoints is a necessary approach that provides an additional and essential layer of complexity to the understanding of cancer genome evolution. Here we employed a technology named Break-seq, with demonstrated efficacy in human lymphoblastoid cell lines [ 4 , 5 ], to map DNA DSBs using massive parallel sequencing. We coupled this DSB mapping with whole-genome DNA sequencing (DNA-seq) to systematically compare spontaneous, but recurrent, DSBs with chromosome structural variant breakpoints. However, the mechanism with which 16q loss is induced is still unclear. Specifically, the precise location of the breakpoint on 16q that leads to its loss has not been described. Therefore, we set out to determine the recurrent DSBs in the MCF-7 cancer genome using Break-seq. We identified 297 recurrent DSBs specifically in the MCF-7 cancer genome. We further identified structural breakpoints, including DNA deletions, amplifications, and translocations, in the MCF-7 genome through DNA-seq analysis, and the associations of gene expression data with these chromosome alterations. These variants, after excluding those involving Y chromosomes, mitochondria sequences and unassigned contigs, were displayed on Circos plots ( Figure 5 A,B). This result suggested that genomic Additionally, one DSB on chr14, spanning 88,889,718 and 88,890,124, was involved in intra-chromosomal translocation, and one DSB on chr11:51,590,333–51,591,355 overlapped with two breakpoints on chr11 that translocated to chr7:132,676,151 and chr8:135,456,020. These results suggest that spontaneous chromosome breakage only accounts for a small fraction of structural changes that lead to chromosomal translocations in the MCF-7 cancer cell line. Nevertheless, the near exclusive overlap between the cancer-specific DSBs and chromosome translocation breakpoints in the pericentromere of 16q underscore the importance of this region in breast cancer development. Consistent with this idea, we found that genes associated with the cancer cell-specific DSBs were enriched in the ER signaling pathways. This result suggests that recurrent DSBs may underlie the transition from normal to luminal B cancer cell in the epithelial cell lineage, and ultimately, the pathophysiology of breast cancer progression. We also investigated the relationship between DSBs and CNV breakpoints to test the hypothesis that recurrent DSBs lead to structural changes in the chromosome. We first verified that MCF-7 (but not MCF-10A) cells underwent 16q loss; however, the sequence loss was confined to approximately half of the 16q arm that is centromere-proximal. Moreover, down-regulation of initiation of replication genes sensitizes tumor cells to anti-cancer treatment [ 45 ]. Therefore, we suggest that SHCBP1 and ORC6 are prime targets for anti-cancer interventions in breast cancer treatment. Our study is the first to combine simultaneous mapping of recurrent DSBs and stable structural breakpoints, along with gene expression, in two well-chosen mammary cell lines. Such a comparison allowed us to specifically test and uncover evidence for recurrent DSBs potentially resulting in structural changes in the chromosome and impacting disease-relevant pathways for breast cancer development.

These mutation types are shown in Figure 14.22. Sometimes a nucleotide is overlooked by the DNA repair system for no known reason. This malignant melanoma is the result of DNA not undergoing repair after too much UV exposure. Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa. Infertility can sometimes be explained by chromosome translocations. Explain how chromosome translocations can cause infertility. Are there times when a chromosome translocation might not result in infertility? The Think About It question is an application of Learning Objective 3.28 and Science Practice 6.2 because students are asked to explain a phenomenon that increases genetic variation.

Acquired chromosome translocations in individuals may either be benign and physiologically asymptomatic or may exert biological consequences and lead to cancer and infertility. In the domestic pig acquired or mosaic translocations are underrepresented, hence their phenotypic and fertility implications are not well understood. This thesis presents the first study of mosaic translocations identified in the domestic pig through routine cytogenetic practices. Routine analysis of the somatic metaphase chromosomes of 5,481 young reproductively unproven boars revealed 32 carriers of mosaic translocations, half of which were carrying a recurrent translocation, mos t(7;9). An additional 7 mosaic translocations were identified through extensive karyotype analysis of relatives of mosaic carriers (n=48) and control animals (n=97). Mosaic translocations in the carriers were phenotypically benign and were recognized to be somatic and confined to hematopoietic cells because mosaicism was not identified in the tissue fibroblast chromosome, fertility of the carriers and pedigree were comparable to breed averages (p>0.05), and cryptic mosaicism was not detected in the pedigree. The results obtained in this study suggest that the incidence of mosaic translocations in Canadian swine is 0.7%, however they impose no observable phenotype or impact on fertility on the carrier animals. Mosaic Reciprocal Chromosome Translocations in Breeding Swine: Prevalence and Potential Biological Implications. Skip to main content Mosaic Reciprocal Chromosome Translocations in Breeding Swine: Prevalence and Potential Biological Implications. Loading... Files Rezaei_Samira_201905_Msc.pdf (7.03 MB) Date 2019-05-06 Authors Rezaei, Samira Journal Title Journal ISSN Volume Title Publisher University of Guelph Abstract Acquired chromosome translocations in individuals may either be benign and physiologically asymptomatic or may exert biological consequences and lead to cancer and infertility. In the domestic pig acquired or mosaic translocations are underrepresented, hence their phenotypic and fertility implications are not well understood. This thesis presents the first study of mosaic translocations identified in the domestic pig through routine cytogenetic practices. Routine analysis of the somatic metaphase chromosomes of 5,481 young reproductively unproven boars revealed 32 carriers of mosaic translocations, half of which were carrying a recurrent translocation, mos t(7;9). An additional 7 mosaic translocations were identified through extensive karyotype analysis of relatives of mosaic carriers (n=48) and control animals (n=97). Mosaic translocations in the carriers were phenotypically benign and were recognized to be somatic and confined to hematopoietic cells because mosaicism was not identified in the tissue fibroblast chromosome, fertility of the carriers and pedigree were comparable to breed averages (p>0.05), and cryptic mosaicism was not detected in the pedigree. The results obtained in this study suggest that the incidence of mosaic translocations in Canadian swine is 0.7%, however they impose no observable phenotype or impact on fertility on the carrier animals. Description Keywords Reciprocal Chromosome Translocations , Mosaic , Moasicism , Swine , Domestic Pig , Cytogenetics , Chromosome Abnormalities , Fertility Citation URI http://hdl.handle.net/10214/15978 License Creative Commons Attribution NonCommercial NoDerivatives 4.0 International Collections Theses & Dissertations (2011 - present) Theses & Dissertations - Harvested by LAC Endorsement Review Supplemented By Referenced By Full item page

gametes) or somatic cells (all cells other than germline cells). Mutations in somatic cells can lead to cancer … on chromosome 17, and the a2 chain is encoded by a gene on chromosome 7. genes, one on chromosome 17 … Nomenclature 107 Lil Chromosome Abnormalities and Pregnancy Loss 120 Abnormalities of Chromosome Structure Abnormalities Favorite Share Flag Flag this item for Graphic Violence Explicit Sexual Content Hate Speech Misinformation/Disinformation Marketing/Phishing/Advertising Misleading/Inaccurate/Missing Metadata texts Medical genetics Publication date 2003 Topics Medical genetics , Hereditary Diseases -- genetics , Genetics, Medical Publisher St. Louis, Mo. : Mosby Collection internetarchivebooks ; inlibrary ; printdisabled Contributor Internet Archive Language English Item Size 1.1G xii, 363 p. : 28 cm Previously cataloged under: Jorde, Lynn B Includes bibliographical references and index Notes Skewed text inherent from the source. Cut off text due too tight binding.