A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns
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The MLH1 c.2252_2253delAA mutation was found in 11 unrelated families from a restricted area south-west of Turin among 140 families with mutations in the mismatch repair genes. The mutation is located in the highly conserved C-terminal region, responsible for dimerization with the PMS2 protein. Twenty-five tumour tissues from 61 individuals with the c.2252_2253delAA mutation were tested for microsatellite instability (MSI) and protein expression. We compared the clinical features of these families versus the rest of our cohort and screened for a founder effect. All but one tumours showed the MSI-high mutator phenotype. Normal, focal and lack of MLH1 staining were observed in 16, 36 and 48 % of tumours, respectively. PMS2 expression was always lost. The mutation co-segregated with Lynch syndrome-related cancers in all informative families. All families but one fulfilled Amsterdam criteria, a frequency higher than in other MLH1 mutants. This was even more evident for AC II (72.7 vs. 57.5 %). Moreover, all families had at least one colon cancer diagnosed before 50 years and one case with multiple Lynch syndrome-related tumours. Interestingly, a statistically significant (p = 0.0057) higher frequency of pancreatic tumours was observed compared to families with other MLH1 mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype analysis demonstrated a common ancestral origin of the mutation, which originated about 1,550 years ago. The mutation is currently classified as having an uncertain clinical significance. Clinical features, tissue analysis and co-segregation with disease strongly support the hypothesis that the MLH1 c.2252_2253delAA mutation has a pathogenic effect.
KeywordsLynch syndrome MLH1 mutations MLH1-PMS2 dimerization Focal immunohistochemical expression Founder effect
We thank Prof. Nicola Migone, for the precious advice and for providing the MLH1 multiple alignment and evolutionary evaluation, Dr. Patrizia Pappi for sequences purification and technical support on microsatellite analysis and Mrs. Katia Pollato for further technical support on IHC and microsatellite analysis.
Conflict of interest
The authors declare no conflict of interest.
- 22.Hamilton SR, Bosman FT, Boffetta P et al (2010) Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system, 4th edn. IARC Press, Lyon, pp 134–146Google Scholar
- 23.Silverberg SG, Kurman RJ, Nogales F, Mutter GL, Kubik-Huch RA, Tavassoli FA (2003) Epithelial tumours and related lesions. In: Tavassoli FA, Devilee P (eds) Pathology and genetics. Tumours of the breast and female genital organs. IARC Press, Lyon, pp 221–232Google Scholar
- 27.Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257PubMedGoogle Scholar
- 42.Caluseriu O, Di Gregorio C, Lucci-Cordisco E et al (2004) 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. J Med Genet 41(3):e34PubMedPubMedCentralCrossRefGoogle Scholar
- 55.Wahlberg SS, Schmeits J, Thomas G, Loda M, Garber J, Syngal S, Kolodner RD, Fox E (2002) Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res 62(12):3485–3492PubMedGoogle Scholar