3 research outputs found
A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns
The MLH1 c.2252_2253delAA mutation was
found in 11 unrelated families from a restricted area southwest
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
tumourswas observed compared to familieswith 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 effec