Dataset Information

Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.

ABSTRACT: The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome.

SUBMITTER: McBride DJ

PROVIDER: S-EPMC3428857 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.

McBride David J DJ Etemadmoghadam Dariush D Cooke Susanna L SL Alsop Kathryn K George Joshy J Butler Adam A Cho Juok J Galappaththige Danushka D Greenman Chris C Howarth Karen D KD Lau King W KW Ng Charlotte K CK Raine Keiran K Teague Jon J Wedge David C DC Cancer Study Group Australian Ovarian AO Caubit Xavier X Stratton Michael R MR Brenton James D JD Campbell Peter J PJ Futreal P Andrew PA Bowtell David Dl DD

The Journal of pathology 20120702 4

The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes a ...[more]

PMID: 22514011

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Project description:BackgroundLTR-retrotransposons (LTR-RT) are a major component of plant genomes and important drivers of genome evolution. Most LTR-RT copies in plant genomes are defective elements found as truncated copies, nested insertions or as part of more complex structures. The recent availability of highly contiguous plant genome assemblies based on long-read sequences now allows to perform detailed characterization of these complex structures and to evaluate their importance for plant genome evolution.ResultsThe detailed analysis of two rice loci containing complex LTR-RT structures showed that they consist of tandem arrays of LTR copies sharing internal LTRs. Our analyses suggests that these LTR-RT tandems are the result of a single insertion and not of the recombination of two independent LTR-RT elements. Our results also suggest that gypsy elements may be more prone to form these structures. We show that these structures are highly polymorphic in rice and therefore have the potential to generate genetic variability. We have developed a computational pipeline (IDENTAM) that scans genome sequences and identifies tandem LTR-RT candidates. Using this tool, we have detected 266 tandems in a pangenome built from the genomes of 76 accessions of cultivated and wild rice, showing that tandem LTR-RT structures are frequent and highly polymorphic in rice. Running IDENTAM in the Arabidopsis, almond and cotton genomes showed that LTR-RT tandems are frequent in plant genomes of different size, complexity and ploidy level. The complexity of differentiating intra-element variations at the nucleotide level among haplotypes is very high, and we found that graph-based pangenomic methodologies are appropriate to resolve these structures.ConclusionsOur results show that LTR-RT elements can form tandem arrays. These structures are relatively abundant and highly polymorphic in rice and are widespread in the plant kingdom. Future studies will contribute to understanding how these structures originate and whether the variability that they generate has a functional impact.

Project description:Cyanobacterium Synechocystis PCC 6803 represents a favored model organism for photosynthetic studies. Its easy transformability allowed construction of a vast number of Synechocystis mutants including many photosynthetically incompetent ones. However, it became clear that there is already a spectrum of Synechocystis "wild-type" substrains with apparently different phenotypes. Here, we analyzed organization of photosynthetic membrane complexes in a standard motile Pasteur collection strain termed PCC and two non-motile glucose-tolerant substrains (named here GT-P and GT-W) previously used as genetic backgrounds for construction of many photosynthetic site directed mutants. Although, both the GT-P and GT-W strains were derived from the same strain constructed and described by Williams in 1988, only GT-P was similar in pigmentation and in the compositions of Photosystem II (PSII) and Photosystem I (PSI) complexes to PCC. In contrast, GT-W contained much more carotenoids but significantly less chlorophyll (Chl), which was reflected by lower level of dimeric PSII and especially trimeric PSI. We found that GT-W was deficient in Chl biosynthesis and contained unusually high level of unassembled D1-D2 reaction center, CP47 and especially CP43. Another specific feature of GT-W was a several fold increase in the level of the Ycf39-Hlip complex previously postulated to participate in the recycling of Chl molecules. Genome re-sequencing revealed that the phenotype of GT-W is related to the tandem duplication of a large region of the chromosome that contains 100 genes including ones encoding D1, Psb28, and other PSII-related proteins as well as Mg-protoporphyrin methylester cyclase (Cycl). Interestingly, the duplication was completely eliminated after keeping GT-W cells on agar plates under photoautotrophic conditions for several months. The GT-W strain without a duplication showed no obvious defects in PSII assembly and resembled the GT-P substrain. Although, we do not exactly know how the duplication affected the GT-W phenotype, we hypothesize that changed stoichiometry of protein components of PSII and Chl biosynthetic machinery encoded by the duplicated region impaired proper assembly and functioning of these multi-subunit complexes. The study also emphasizes the crucial importance of a proper control strain for evaluating Synechocystis mutants.

Project description:BackgroundThe causes of breast cancer are poorly understood. A potential risk factor is Epstein-Barr virus (EBV), a lifelong infection nearly everyone acquires. EBV-transformed human mammary cells accelerate breast cancer when transplanted into immunosuppressed mice, but the virus can disappear as malignant cells reproduce. If this model applies to human breast cancers, then they should have genome damage characteristic of EBV infection.ObjectiveThis study tests the hypothesis that EBV infection predisposes one to breast cancer by causing permanent genome damage that compromises cancer safeguards.MethodsPublicly available genome data from approximately 2100 breast cancers and 25 ovarian cancers were compared to cancers with proven associations to EBV, including 70 nasopharyngeal cancers, 90 Burkitt lymphomas, 88 diffuse large B-cell lymphomas, and 34 gastric cancers. Calculation algorithms to make these comparisons were developed.ResultsChromosome breakpoints in breast and ovarian cancer clustered around breakpoints in EBV-associated cancers. Breakpoint distributions in breast and EBV-associated cancers on some chromosomes were not confidently distinguished (P>.05), but differed from controls unrelated to EBV infection. Viral breakpoint clusters occurred in high-risk, sporadic, and other breast cancer subgroups. Breakpoint clusters disrupted gene functions essential for cancer protection, which remain compromised even if EBV infection disappears. As CRISPR (clustered regularly interspaced short palindromic repeats)-like reminders of past infection during evolution, EBV genome fragments were found regularly interspaced between Piwi-interacting RNA (piRNA) genes on chromosome 6. Both breast and EBV-associated cancers had inactivated genes that guard piRNA defenses and the major histocompatibility complex (MHC) locus. Breast and EBV-associated cancer breakpoints and other variations converged around the highly polymorphic MHC. Not everyone develops cancer because MHC differences produce differing responses to EBV infection. Chromosome shattering and mutation hot spots in breast cancers preferentially occurred at incorporated viral sequences. On chromosome 17, breast cancer breakpoints that clustered around those in EBV-mediated cancers were linked to estrogen effects. Other breast cancer breaks affected sites where EBV inhibits JAK-STAT and SWI-SNF signaling pathways. A characteristic EBV-cancer gene deletion that shifts metabolism to favor tumors was also found in breast cancers. These changes push breast cancer into metastasis and then favor survival of metastatic cells.ConclusionsEBV infection predisposes one to breast cancer and metastasis, even if the virus disappears. Identifying this pathogenic viral damage may improve screening, treatment, and prevention. Immunizing children against EBV may protect against breast, ovarian, other cancers, and potentially even chronic unexplained diseases.

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Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.

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Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.

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