Skip to main content

Advertisement

Log in

The Value of Multi-Modal Gene Screening in HNPCC in Quebec: Three Mutations in Mismatch Repair Genes that would have not been Correctly Identified by Genomic DNA Sequencing Alone

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by a mutation in one of the mismatch repair genes, most frequently MLH1 or MSH2. The rate of mutation detection is influenced by many factors, including the diagnostic methods used. Large deletions, which occur frequently in MLH1 and MSH2, are not detected by exon-by-exon screening methods. Here, we describe three mutations in mismatch repair genes detected using a screening protocol that combines protein truncation test (PTT) analysis and multiplex ligation-dependent probe amplification (MLPA) with genomic and cDNA sequencing. Two of these mutations consist of large deletions in MLH1 that were detected by both MLPA and PTT but that would have been missed by genomic DNA sequencing. The third is a large deletion in MSH2 that could not be detected by PTT because of its location relative to the primers used to amplify the cDNA, or by sequencing. This mutation was detected by MLPA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CRC:

colorectal cancer

DHPLC:

denaturing high performance liquid chromatography

DSB:

double stranded break

HNPCC:

hereditary non-polyposis colorectal cancer

LTR:

long terminal repeat

MLPA:

multiplex ligation-dependent probe amplification

MMR:

mismatch repair

NHEJ:

non-homologous end joining

NHR:

non-homologous recombination

PTT:

protein truncation test

SINE:

short interspersed nuclear element

SSCP:

single strand conformational polymorphism

References

  1. G Casey NM Lindor N Papadopoulos et al. (2005) ArticleTitleConversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer JAMA 293 IssueID7 799–809 Occurrence Handle10.1001/jama.293.7.799 Occurrence Handle1:CAS:528:DC%2BD2MXhsVyjtLw%3D Occurrence Handle15713769

    Article  CAS  PubMed  Google Scholar 

  2. MC Luce G Marra DP Chauhan et al. (1995) ArticleTitleIn vitro transcription/translation assay for the screening of hMLH1 and hMSH2 mutations in familial colon cancer Gastroenterology 109 IssueID4 1368–74 Occurrence Handle10.1016/0016-5085(95)90600-2 Occurrence Handle1:CAS:528:DyaK2MXos1aqu70%3D Occurrence Handle7557107

    Article  CAS  PubMed  Google Scholar 

  3. RD Kolodner NR Hall J Lipford et al. (1994) ArticleTitleStructure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations Genomics 24 IssueID3 516–26 Occurrence Handle10.1006/geno.1994.1661 Occurrence Handle1:CAS:528:DyaK2MXjtVelsrg%3D Occurrence Handle7713503

    Article  CAS  PubMed  Google Scholar 

  4. RD Kolodner NR Hall J Lipford et al. (1995) ArticleTitleStructure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations Cancer Res 55 IssueID2 242–8 Occurrence Handle1:CAS:528:DyaK2MXjtFyjs7s%3D Occurrence Handle7812952

    CAS  PubMed  Google Scholar 

  5. CF Taylor RS Charlton J Burn et al. (2003) ArticleTitleGenomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA Hum Mutat 22 IssueID6 428–33 Occurrence Handle10.1002/humu.10291 Occurrence Handle1:CAS:528:DC%2BD2cXps1Kl Occurrence Handle14635101

    Article  CAS  PubMed  Google Scholar 

  6. P Hutter A Couturier C Rey-Berthod (2000) ArticleTitleTwo common forms of the human MLH1 gene may be associated with functional differences J Med Genet 37 IssueID10 776–81 Occurrence Handle10.1136/jmg.37.10.776 Occurrence Handle1:CAS:528:DC%2BD3cXnvVOis78%3D Occurrence Handle11015456

    Article  CAS  PubMed  Google Scholar 

  7. Y Wang W Friedl C Lamberti et al. (2003) ArticleTitleHereditary nonpolyposis colorectal cancer: Frequent occurrence of large genomic deletions in MSH2 and MLH1 genes Int J Cancer 103 IssueID5 636–41 Occurrence Handle10.1002/ijc.10869 Occurrence Handle1:CAS:528:DC%2BD3sXmtFKnsg%3D%3D Occurrence Handle12494471

    Article  CAS  PubMed  Google Scholar 

  8. M Nystrom-Lahti P Kristo NC Nicolaides et al. (1995) ArticleTitleFounding mutations and Alu-mediated recombination in hereditary colon cancer Nat Med 1 IssueID11 1203–6 Occurrence Handle1:CAS:528:DyaK2MXptFahsLs%3D Occurrence Handle7584997

    CAS  PubMed  Google Scholar 

  9. A Viel F Petronzelli PL Della et al. (2002) ArticleTitleDifferent molecular mechanisms underlie genomic deletions in the MLH1 Gene Hum Mutat 20 IssueID5 368–74 Occurrence Handle10.1002/humu.10138 Occurrence Handle1:CAS:528:DC%2BD38XptV2nu70%3D Occurrence Handle12402334

    Article  CAS  PubMed  Google Scholar 

  10. B Marshall G Isidro MG Boavida (1996) ArticleTitleInsertion of a short Alu sequence into the hMSH2 gene following a double cross over next to sequences with chi homology Gene 174 IssueID1 175–9 Occurrence Handle10.1016/0378-1119(96)00515-X Occurrence Handle1:CAS:528:DyaK28XmtV2iurw%3D Occurrence Handle8863745

    Article  CAS  PubMed  Google Scholar 

  11. LK Su G Steinbach JC Sawyer et al. (2000) ArticleTitleGenomic rearrangements of␣the APC tumor-suppressor gene in familial adenomatous polyposis Hum Genet 106 IssueID1 101–7 Occurrence Handle10.1007/s004390051016 Occurrence Handle1:CAS:528:DC%2BD3cXhvVemsL0%3D Occurrence Handle10982189

    Article  CAS  PubMed  Google Scholar 

  12. D Gebow N Miselis HL Liber (2000) ArticleTitleHomologous and nonhomologous recombination resulting in deletion: Effects of p53 status, microhomology, and repetitive DNA length and orientation Mol Cell Biol 20 IssueID11 4028–35 Occurrence Handle10.1128/MCB.20.11.4028-4035.2000 Occurrence Handle1:CAS:528:DC%2BD3cXjt1Cmtr4%3D Occurrence Handle10805745

    Article  CAS  PubMed  Google Scholar 

  13. SJ Chen Z Chen MP Font et al. (1989) ArticleTitleStructural alterations of the BCR and ABL genes in Ph1 positive acute leukemias with rearrangements in the BCR gene first intron: Further evidence implicating Alu sequences in the chromosome translocation Nucleic Acids Res 17 IssueID19 7631–42 Occurrence Handle1:CAS:528:DyaL1MXmt1KnsLw%3D Occurrence Handle2678002

    CAS  PubMed  Google Scholar 

  14. N Chuzhanova SS Abeysinghe M Krawczak DN Cooper (2003) ArticleTitleTranslocation, gross deletion breakpoints in human inherited disease, cancer II: Potential involvement of repetitive sequence elements in secondary structure formation between DNA ends Hum Mutat 22 IssueID3 245–51 Occurrence Handle10.1002/humu.10253 Occurrence Handle1:CAS:528:DC%2BD3sXos12msb4%3D Occurrence Handle12938089

    Article  CAS  PubMed  Google Scholar 

  15. K Valerie LF Povirk (2003) ArticleTitleRegulation and mechanisms of mammalian double-strand break repair Oncogene 22 IssueID37 5792–812 Occurrence Handle10.1038/sj.onc.1206679 Occurrence Handle1:CAS:528:DC%2BD3sXmslemt7g%3D Occurrence Handle12947387

    Article  CAS  PubMed  Google Scholar 

  16. M Honma M Izumi M Sakuraba et al. (2003) ArticleTitleDeletion, rearrangement, and gene conversion; genetic consequences of chromosomal double-strand breaks in human cells Environ Mol Mutagen 42 IssueID4 288–98 Occurrence Handle10.1002/em.10201 Occurrence Handle1:CAS:528:DC%2BD2cXlsFSjtw%3D%3D Occurrence Handle14673874

    Article  CAS  PubMed  Google Scholar 

  17. SP Lees-Miller K Meek (2003) ArticleTitleRepair of DNA double strand breaks by non-homologous end joining Biochimie 85 IssueID11 1161–73 Occurrence Handle10.1016/j.biochi.2003.10.011 Occurrence Handle1:CAS:528:DC%2BD2cXjsVyqsw%3D%3D Occurrence Handle14726021

    Article  CAS  PubMed  Google Scholar 

  18. DB Roth TN Porter JH Wilson (1985) ArticleTitleMechanisms of nonhomologous recombination in mammalian cells Mol Cell Biol 5 IssueID10 2599–607 Occurrence Handle1:CAS:528:DyaL2MXlslegsLo%3D Occurrence Handle3016509

    CAS  PubMed  Google Scholar 

  19. KC Little P Chartrand (2004) ArticleTitleGenomic DNA is captured and amplified during double-strand break (DSB) repair in human cells Oncogene 23 IssueID23 4166–72 Occurrence Handle10.1038/sj.onc.1207570 Occurrence Handle1:CAS:528:DC%2BD2cXktVyju7s%3D Occurrence Handle15048077

    Article  CAS  PubMed  Google Scholar 

  20. DB Roth XB Chang JH Wilson (1989) ArticleTitleComparison of filler DNA at immune, nonimmune, and oncogenic rearrangements suggests multiple mechanisms of formation Mol Cell Biol 9 IssueID7 3049–57 Occurrence Handle1:CAS:528:DyaL1MXkslags7w%3D Occurrence Handle2550794

    CAS  PubMed  Google Scholar 

  21. DB Roth GN Proctor LK Stewart JH Wilson (1991) ArticleTitleOligonucleotide capture during end joining in mammalian cells Nucleic Acids Res 19 IssueID25 7201–05 Occurrence Handle1:CAS:528:DyaK38XhtVSmtrc%3D Occurrence Handle1662811

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William D Foulkes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McVety, S., Li, L., Thiffault, I. et al. The Value of Multi-Modal Gene Screening in HNPCC in Quebec: Three Mutations in Mismatch Repair Genes that would have not been Correctly Identified by Genomic DNA Sequencing Alone. Familial Cancer 5, 21–28 (2006). https://doi.org/10.1007/s10689-005-2572-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-005-2572-6

Keywords

Navigation