NDLI: A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

Content Provider	Springer Nature Link
Author	Borelli, Iolanda Casalis Cavalchini, Guido C. Del Peschio, Serena Micheletti, Monica Venesio, Tiziana Sarotto, Ivana Allavena, Anna Delsedime, Luisa Barberis, Marco A. Mandrile, Giorgia Berchialla, Paola Ogliara, Paola Bracco, Cecilia Pasini, Barbara
Copyright Year	2014
Abstract	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.
Starting Page	401
Ending Page	413
Page Count	13
File Format	PDF
ISSN	13899600
Journal	Familial Cancer
Volume Number	13
Issue Number	3
e-ISSN	15737292
Language	English
Publisher	Springer Netherlands
Publisher Date	2014-05-07
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Lynch syndrome MLH1 mutations MLH1-PMS2 dimerization Focal immunohistochemical expression Founder effect Cancer Research Human Genetics Epidemiology Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Genetics Cancer Research Genetics (clinical) Oncology

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