Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families

Montagna, Marco; Santacatterina, Maria; Torri, Arianna; Menin, Chiara; Zullato, Daniela; Chieco‐Bianchi, Luigi; D’Andrea, Emma

doi:10.1038/sj.onc.1202754

Cited by 91 publications

(70 citation statements)

References 11 publications

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“…69 In addition, Alu sequences have been identified at BRCA1 breakpoints in breast/ovarian cancer families. 70 In addition to silent (AgNOR-negative) rDNA discussed above, HDLM and KM-H2 cells amplify AgNOR-positive rDNA present in markers. A positive association between AgNOR activity and tumor stage in HD has been reported.…”

Section: Possible Roles For Rdna Changesmentioning

confidence: 99%

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

MacLeod

Spitzer

Bar‐Am³

et al. 2000

Leukemia

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Although the neoplastic significance of the chromosome changes widespread in Hodgkin's disease (HD) remains obscure, a distinct cytogenetic picture has emerged combining aneuploidy with structural rearrangements clustered at certain breakpoints. Notably absent are the recurrent chromosome translocations which distinguish other hematopoietic neoplasms and serve as clues to underlying oncogene alterations. The paucity of neoplastic cells in HD biopsies hinders detailed chromosome analysis. As an alternative, we investigated a panel of well characterized cell lines by classical and molecular cytogenetics, using single-gene and subtelomeric probes, including three autologous HD examples (HDLM-1/2/3) analyzed by 'spectral karyotyping' -the first complete HD karyotype to be documented. Although complex, most rearrangements in HDLM cells arose in vivo and included few rare but many typical HD breakpoints, notably at the r(ibosomal)DNA regions. Two types of genomic rearrangement involving DNA repeats were conspicuous: insertion and genomic amplification/coamplification of rDNA -the first genomic rDNA rearrangements to be reported in a tumor cell, and the first example of multiple 'jumping translocations' (JT). Of four subtelomeric microsatellite repeats tested in HDLM cells, three exhibited interstitial sites at JT, of which two (at 5qter and 9pter) were respectively associated with deletion of the 5q31-32 myeloid region, and coamplification of a recently described HD-recurrent amplicon at 9p2 together with transcriptionally silent rDNA. Altogether, three out of four HD cell lines carried interstitial 9p subtelomeres and rDNA rearrangements. Taken together, these data suggest tumorigenic rearrangements may be facilitated by 'hitchhiking' along with mobile DNA repeat sequences which may target gene rearrangement at 9p in HD. Southern analysis of parallel rearrangements within rDNA intergenic spacers in HDLM cells highlighted several at, or near, retroposons. As well as validating HD cell lines as cytogenetic models, and resources for identifying genes rearranged in HD, our findings warrant further investigation of the roles of DNA repeat sequences, notably subtelomeric microsatellites, rDNA spacer sequences and retroposons as facilitators and markers of tumor-gene rearrangement.

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Section: Possible Roles For Rdna Changesmentioning

confidence: 99%

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

MacLeod

Spitzer

Bar‐Am³

et al. 2000

Leukemia

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“…These conventional screening procedures, however, neglect a class of mutations: large genomic rearrangements. Several large germline deletions and one large germline duplication in BRCA1 have been reported Petrij-Bosch et al, 1997;Montagna et al, 1999;Carson et al, 1999;Rohlfs et al, 1999). All of the large germline rearrangements were undetectable by conventional genomic DNA (gDNA) screening procedures (Table 1.2).…”

Section: Germline and Somatic Alterations In Brca1mentioning

confidence: 99%

“…Eleven large germline deletions and one large germline duplication of BRCA1 have been characterized since that time PetrijBosch et al, 1997;Montagna et al, 1999, Carson et al, 1999Rohlfs et al, 1999;and this study). Of the 24 breakpoints involved, 20 occurred in Alu sequence.…”

Section: Large Germline Rearrangements Of Brc'almentioning

confidence: 99%

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Transcriptional Regulation of BRCA1

Payne¹,

King²

1999

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Publte reporting burden (or this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget,, Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE October 20003. REPORT TYPE AND DATES COVERED Final (15 Sep 9? -14 Sep_00) TITLE AND SUBTITLE Transcriptional Regulation of BRCAl AUTHOR(S)Shannon R. Payne, Ph.D. Mary Claire King, Ph.D. FUNDING NUMBERS DAMD17-97-1-7210 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Washington Seattle, Washington 98105-6613 E-MAIL:spayne@u.washington, edu 8. PERFORMING ORGANIZATION REPORT NUMBER Germline mutations in BRCAl lead to an increased risk of breast and ovarian cancer, with loss of the second, normal allele critical to tumorigenesis. It was widely presumed that the cloning and characterization of genes involved in hereditary breast cancer would lead to a better understanding of the genesis of the more common non-inherited forms of breast cancer. The relative lack of somatic mutations found in BRCAl, however, has argued against its involvement in non-inherited breast cancer. Our research specifically addresses whether large genomic rearrangements are responsible for somatic inactivation of BRCAl. We characterized the types of large germline rearrangements that occur within the BRCAl region and investigated the contribution of two large germline rearrangements to breast cancer in a population-based series of breast cancer patients. In order to determine whether BRCAl is inactivated somatically by large rearrangement of BRCAl, we analyzed 92 breast carcinomas using loss of heterozygosity analysis, Long PCR, Southern analysis, and immunohistochemistry. Although two large germline rearrangements were detected in our series, no large somatic rearrangements were identified. As previously reported BRCAl protein was reduced in the majority of breast tumors of high histologic grade. Interestingly, reduced BRCAl protein in sporadic breast carcinomas was significantly associated with loss of the most 5' BRCAl intragenic marker. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U14. SUBJECT TERMS In Family 5, previous analysis of cDNA revealed germline deletion of exon 3 (codon 27 stop), cosegregating with 10 cases of breast and ovarian cancer (Friedman et al., 1994. Nat Genet., 8:399); the genomic basis of the mRNA deletion remained unknown. Long-range PCR, using an exon 3 forward/"exon 4" reverse primer pair designed from BRCA1 genomic sequence (gb L78833), reveals a 1039 bp genomic deletion involving part of exon 3 and pa...

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“…In tumours, it has been shown that there is a high density of mobile elements at some tumour specific breakpoints and these may facilitate cancer-inducing structural rearrangements such as deletions, duplications or translocations (Mauillon et al, 1996;Montagna et al, 1999;Rowe et al, 1995;Strout et al, 1998). Given their nature, the activity of transposable elements is mostly suppressed by epigenetic mechanisms at transcriptional and post-transcriptional levels (Slotkin and Martienssen, 2007;Yang and Kazazian, 2006).…”

Section: Mobile Dna Elements At Rearrangement Breakpointsmentioning

confidence: 99%

Structural variation in cancer genomes & the identification of personalized DNA-based cancer biomarkers

Quek¹

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Cancer is the result of the accumulation of genetic and epigenetic alterations in key genes, which ultimately lead to uncontrolled growth of mutated cells. Genetic alterations range from small base substitutions to large chromosomal structural rearrangements. Many cancer genomes carry tens to hundreds of somatic structural rearrangements, which may have functional consequences. However, the patterns and characterization of somatic rearrangements in human cancers are still in early stages. In this thesis, I describe the genomic landscape of somatic structural rearrangements in human pancreatic cancers. I then investigate the potential mechanisms involved in somatic rearrangement formation and test whether such rearrangements can be used as biomarkers to monitor patient therapy.Chapter 1 -Introduction: This chapter is a broad overview of somatic structural rearrangements in human cancers, motivation for studying them, and their potential use for clinical applications. suggesting that the formation of somatic rearrangements could also be mediated by either retrotransposition activity or chromosomal fragile sites. Taken together, the analyses of breakpoint junctions highlighted that the formation of somatic rearrangements in pancreatic carcinogenesis is complex -potentially with more than one mechanism active within a cancer genome. Chapter 4 -Identification of personalized DNA-based biomarkers for pancreaticcancer and the assessment of whether they can be used to monitor tumour burden and response to chemotherapy: In this chapter, I first evaluated the performance of sequencing and PCR based methods to detect ctDNA. Subsequently, I quantified ctDNA in the serum or plasma of the three pancreatic cancer patients. Little or no detection of ctDNA was observed in the analysed serum samples. For one patient, a tumour specific rearrangement was detected in the serum, and this patient had already presented with metastatic disease. Based on the results, it was hypothesized that ctDNA released from pancreatic cancer might be limited by: i) nature of pancreatic cancer; ii) the physiological location of the pancreas which could influence the amount of ctDNA released in the circulation, as the fragmented tumour DNA might be cleared by the liver and therefore reduced the opportunity to detect ctDNA in the circulation; iii) volume of plasma or serum used to isolate cfDNA; iv) the status of disease progression. In this analysis, the ctDNA was detected only in the sample collected at late stage pancreatic cancer (after the diagnosed of liver metastasis). Thus, in the context of pancreatic cancer disease, the quantification of ctDNA might be more suitable for recurrent disease, which has metastasized from the pancreas.Chapter 5: I concluded my findings throughout my studies in Chapter 2, 3 and 4 with a summary and future directions.iv | P a g e

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Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families

Cited by 91 publications

References 11 publications

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

Transcriptional Regulation of BRCA1

Structural variation in cancer genomes & the identification of personalized DNA-based cancer biomarkers

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