Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer

Article metrics

Abstract

Numerous reports have highlighted the contribution of MSH2 and MLH1 genomic deletions to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch's syndrome, but genomic duplications of these genes have been rarely reported. Using quantitative multiplex PCR of short fluorescent fragments (QMPSF), 962 and 611 index cases were, respectively, screened for MSH2 and MLH1 genomic rearrangements. This allowed us to detect, in 11 families, seven MSH2 duplications affecting exons 1–2–3, exons 4–5–6, exon 7, exons 7–8, exons 9–10, exon 11, and exon 15, and three MLH1 duplications affecting exons 2–3, exon 4 and exons 6–7–8. All duplications were confirmed by an independent method. The contribution of genomic duplications of MSH2 and MLH1 to HNPCC can therefore be estimated approximately to 1% of the HNPCC cases. Although this frequency is much lower than that of genomic deletions, the presence of MSH2 or MLH1 genomic duplications should be considered in HNPCC families without detectable point mutations.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1

References

  1. 1

    Gruber SB : New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 2006; 130: 577–587.

  2. 2

    Nystrom-Lahti M, Kristo P, Nicolaides NC et al: Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med 1995; 1: 1203–1206.

  3. 3

    Mauillon JL, Michel P, Limacher JM et al: Identification of novel germline hMLH1 mutations including a 22 kb Alu-mediated deletion in patients with familial colorectal cancer. Cancer Res 1996; 56: 5728–5733.

  4. 4

    Wijnen J, van der Klift H, Vasen H et al: MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 1998; 20: 326–328.

  5. 5

    Charbonnier F, Raux G, Wang Q et al: Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 2000; 60: 2760–2763.

  6. 6

    Charbonnier F, Olschwang S, Wang Q et al: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 2002; 62: 848–853.

  7. 7

    Gille JJ, Hogervorst FB, Pals G et al: Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. Br J Cancer 2002; 87: 892–897.

  8. 8

    Nakagawa H, Hampel H, de la Chapelle A : Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques. Hum Mutat 2003; 22: 258.

  9. 9

    Viel A, Petronzelli F, Della Puppa L et al: Different molecular mechanisms underlie genomic deletions in the MLH1 Gene. Hum Mutat 2002; 20: 368–374.

  10. 10

    Taylor CF, Charlton RS, Burn J, Sheridan E, Taylor GR : Genomic 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 2003; 22: 428–433.

  11. 11

    Wang Y, Friedl W, Lamberti C et al: Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer 2003; 103: 636–641.

  12. 12

    Wagner A, Barrows A, Wijnen JT et al: Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 2003; 72: 1088–1100.

  13. 13

    Di Fiore F, Charbonnier F, Martin C et al: Screening for genomic rearrangements of the MMR genes must be included in the routine diagnosis of HNPCC. J Med Genet 2004; 41: 18–20.

  14. 14

    Bunyan DJ, Eccles DM, Sillibourne J et al: Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification. Br J Cancer 2004; 91: 1155–1159.

  15. 15

    Casey G, Lindor NM, Papadopoulos N et al: Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. JAMA 2005; 293: 799–809.

  16. 16

    Zhu M, Li J, Zhang X et al: Large genomic aberrations in MSH2 and MLH1 genes are frequent in Chinese colorectal cancer. Cancer Genet Cytogenet 2005; 160: 61–67.

  17. 17

    Castellvi-Bel S, Castells A, Strunk M et al: Genomic rearrangements in MSH2 and MLH1 are rare mutational events in Spanish patients with hereditary nonpolyposis colorectal cancer. Cancer Lett 2005; 225: 93–98.

  18. 18

    Charbonnier F, Baert-Desurmont S, Liang P et al: The 5′ region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences. Hum Mutat 2005; 26: 255–261.

  19. 19

    Baudhuin LM, Ferber MJ, Winters JL et al: Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 2005; 129: 846–854.

  20. 20

    Li L, McVety S, Younan R et al: Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC). Hum Mutat 2006; 27: 388.

  21. 21

    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. Fam Cancer 2006; 5: 21–28.

  22. 22

    Spaepen M, Vankeirsbilck B, Van Opstal S et al: Germline Mutations of the hMLH1 and hMSH2 Mismatch Repair Genes in Belgian Hereditary Nonpolyposis Colon Cancer (HNPCC) Patients. Fam Cancer 2006; 5: 179–189.

  23. 23

    Kurzawski G, Suchy J, Lener M et al: Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). Clin Genet 2006; 69: 40–47.

  24. 24

    Niessen RC, Berends MJ, Wu Y et al: Identification of mismatch repair gene mutations in young colorectal cancer patients and patients with multiple HNPCC-associated tumours. Gut 2006; 55: 1781–1788.

  25. 25

    Nakagawa H, Yan H, Lockman J et al: Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements. Cancer Res 2002; 62: 4579–4582.

  26. 26

    Vasen HF, Watson P, Mecklin JP, Lynch HT : New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116: 1453–1456.

  27. 27

    Casilli F, Di Rocco ZC, Gad S et al: Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments. Hum Mutat 2002; 20: 218–226.

  28. 28

    Tournier I, Paillerets BB, Sobol H et al: Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res 2004; 64: 8143–8147.

  29. 29

    Rovelet-Lecrux A, Hannequin D, Raux G et al: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 2006; 38: 24–26.

Download references

Acknowledgements

We thank our colleagues from the French HNPCC consortium, especially Pascaline Berthet, Olivier Caron, Philippe Gorry, Dominique Leroux, Michel Longy, Rosette Lidereau. This work was supported by a grant from the French National Cancer Institute (INCA) to the Northwest Canceropole.

Author information

Correspondence to Thierry Frebourg.

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • HNPCC
  • Lynch's syndrome
  • MSH2
  • MLH1
  • QMPSF
  • duplication

Further reading