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Germline CDH1 deletions in hereditary diffuse gastric cancer families

By Carla Oliveira, Janine Senz, Pardeep Kaurah, Hugo Pinheiro, Remo Sanges, Anne Haegert, Giovanni Corso, Jan Schouten, Rebecca Fitzgerald, Holger Vogelsang, Gisela Keller, Sarah Dwerryhouse, Donna Grimmer, Suet-Feung Chin, Han-Kwang Yang, Charles E. Jackson, Raquel Seruca, Franco Roviello, Elia Stupka, Carlos Caldas and David Huntsman

Abstract

Germline CDH1 point or small frameshift mutations can be identified in 30–50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT–PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is ∼46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families

Topics: Articles
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:2667284
Provided by: PubMed Central
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    Citations

    1. (2008). A familial inverted duplication/deletion of 2p25.1-25.3 provides new clues on the genesis of inverted duplications.
    2. (2006). A Novel Type of Deletion in the CDKN2A Gene Identified in a Melanoma-Prone Family. Genes Chrom.
    3. (2001). C.International Gastric Cancer Linkage Consortium
    4. (2005). Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.
    5. (2005). Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients.
    6. (2006). Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.
    7. (1997). Cryptic signals and the fidelity of V(D)J joining.
    8. (2005). Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer.
    9. (1999). Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation.
    10. (2005). Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome).
    11. (1996). Distinct DNA sequence and structure requirements for the two steps of V(D)J recombination signal cleavage.
    12. (2004). E-Cadherin (CDH1) and TP53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients.
    13. (1998). E-cadherin germline mutations in familial gastric cancer.
    14. (2001). E-cadherin is not frequently mutated in hereditary gastric cancer.
    15. (2001). Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations.
    16. (2008). Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer.
    17. (2004). Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions.
    18. (1999). Familial gastric cancer: overview and guidelines for management.
    19. (2007). Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.
    20. (1991). Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment.
    21. (2006). Genetics, pathology, and clinics of familial gastric cancer.
    22. (2007). Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations.
    23. (1999). Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.
    24. (2001). Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated?
    25. (2004). Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.
    26. (2008). Germline translocations in mice: unique tools for analyzing gene function and long-distance regulatory mechanisms.
    27. (2007). Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family.
    28. (2008). Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy.
    29. (2001). Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin.
    30. (2003). Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques.
    31. (2006). Identification of Alu elements mediating a partial PMP22deletion.
    32. (1998). Identification of germ-line E-cadherin mutations in gastric cancer families of European origin.
    33. (2004). Intragenic deletion of CDH-1 as the inactivating mechanism of the wild-type allele in a HDGC tumor.
    34. (2007). Ionizing radiation and restriction enzymes induce microhomology-mediated illegitimate recombination in Saccharomyces cerevisiae.
    35. (2005). Large deletions of the APC Gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study.
    36. (2006). Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark.
    37. (2008). Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer.
    38. (1998). MSH2 genomic deletions are a frequent cause of HNPCC.
    39. (2002). MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer.
    40. (2007). Paired-end mapping reveals extensive structural variation in the human genome.
    41. (2002). Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification.
    42. (2007). Saccharomyces cerevisiae Sae2- and Tel1-dependent single-strand DNA formation at DNA break promotes microhomology-mediated end joining.
    43. (2002). Screening of E-Cadherin in gastric cancer families reveals germ-line mutations only in hereditary diffuse gastric cancer kindred.
    44. (2008). Small deletion variants have 1554 Human Molecular Genetics,
    45. (2006). The contribution of germline rearrangements to the spectrum of BRCA2 mutations.
    46. (2008). The fine-scale and complex architecture of human copy-number variation.
    47. (2004). to genetic predisposition in German gastric cancer patients.

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