title: A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns.
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.
authors.affiliation: Department of Medical Sciences, University of Turin, Via Santena 19 Torino, 10126, Turin, Italy, iolanda.borelli@unito.it.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Borelli
authors.forename: Guido C
authors.initials: GC
authors.lastname: Casalis Cavalchini
authors.forename: Serena
authors.initials: S
authors.lastname: Del Peschio
authors.forename: Monica
authors.initials: M
authors.lastname: Micheletti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Venesio
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Anna
authors.initials: A
authors.lastname: Allavena
authors.forename: Luisa
authors.initials: L
authors.lastname: Delsedime
authors.forename: Marco A
authors.initials: MA
authors.lastname: Barberis
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.forename: Paola
authors.initials: P
authors.lastname: Berchialla
authors.forename: Paola
authors.initials: P
authors.lastname: Ogliara
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bracco
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1