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A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability
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  1. O Caluseriu1,6,
  2. C Di Gregorio2,
  3. E Lucci-Cordisco1,
  4. M Santarosa3,
  5. J Trojan4,
  6. A Brieger4,
  7. P Benatti5,
  8. M Pedroni5,
  9. T Colibazzi1,9,
  10. A Bellacosa1,7,
  11. G Neri1,
  12. M Ponz de Leon5,
  13. A Viel3,
  14. M Genuardi1,8
  1. 1Department of Medical Genetics, “A. Gemelli” School of Medicine, Catholic University, Rome, Italy
  2. 2Department of Histopathology, Carpi Hospital, Carpi, Italy
  3. 3Division of Experimental Oncology 1, CRO-IRCCS, Aviano, Italy
  4. 4Department of Internal Medicine, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
  5. 5Department of Internal Medicine, University of Modena and Reggio Emilia, Italy
  6. 6Present address: Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, ON, Canada
  7. 7Present address: Human Genetics Program, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA
  8. 8Present address: Section of Medical Genetics, Department of Clinical Pathophysiology, University of Florence, Italy
  9. 9Present address: McGaw Medical Center of Northwestern University Chicago, IL
  1. Correspondence to:
 Maurizio Genuardi MD
 Sezione di Genetica Medica, Dipartimento di Fisiopatologia Clinica, Università degli Studi di Firenze, Viale G. Pieraccini 6, 50139 Florence, Italy; m.genuardidfc.unifi.it

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Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal dominant condition predisposing to tumours of the large bowel and other sites. In HNPCC, cancer predisposition is usually inherited as a highly penetrant trait, with a tendency to the development of multiple tumours. Clinical diagnosis of HNPCC is based on the so-called modified “Amsterdam criteria”,1 which include: (a) the presence of at least three family members—one of whom must be a first degree relative to two other members—affected with carcinoma of the colon, rectum, endometrium, small bowel, or urothelium; (b) a direct transmission of the disease from parent to child; (c) the occurrence of at least one tumour before the patient reaches 50 years of age; and (d) the exclusion of a diagnosis of familial adenomatous polyposis.

The genetic defects underlying most HNPCC cases are represented by constitutional point mutations of one of several genes encoding for proteins of the DNA mismatch repair complex. The vast majority of mutations are located in the major mismatch repair genes MSH2 and MLH1 (International Collaborative Group on HNPCC Mutation Database). The constitutional defects most commonly identified are nonsense, splice-site, or frameshift alterations, which all predict the synthesis of shorter, non-functional proteins. Tumours arising in carriers of mismatch repair gene mutations are characterised by a high frequency of insertion or deletion type somatic mutations within microsatellite repeats.2 These are the expression of mismatch repair deficiency, which arises when a second somatic mutation affecting the wild-type allele fully inactivates the gene locus already altered in the germline.3 Inactivation of a specific mismatch repair locus in a HNPCC tumour is often revealed by immunohistochemical methods, which show absence of nuclear staining following incubation with antibodies against the mismatch repair protein encoded by the mutant gene.4

In addition to genetic heterogeneity, HNPCC …

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