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\ud found in 11 unrelated families from a restricted area southwest\ud of Turin among 140 families with mutations in the\ud mismatch repair genes. The mutation is located in the highly\ud conserved C-terminal region, responsible for dimerization\ud with the PMS2 protein. Twenty-five tumour tissues from 61\ud individuals with the c.2252_2253delAA mutation were tested\ud for microsatellite instability(MSI) and protein expression.We\ud compared the clinical features of these families versus the rest\ud of our cohort and screened for a founder effect. All but one\ud tumours showed the MSI-high mutator phenotype. Normal,\ud focal and lack of MLH1 staining were observed in 16, 36 and\ud 48 % of tumours, respectively. PMS2 expression was always\ud lost. The mutation co-segregated with Lynch syndrome-related\ud cancers in all informative families. All families but one\ud fulfilled Amsterdam criteria, a frequency higher than in other\ud MLH1 mutants. This was even more evident for AC II (72.7\ud vs. 57.5 %). Moreover, all families had at least one colon\ud cancer diagnosed before 50 years and one case with multiple\ud Lynch syndrome-related tumours. Interestingly, a statistically\ud significant (p = 0.0057) higher frequency of pancreatic\ud tumourswas observed compared to familieswith other MLH1\ud mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype\ud analysis demonstrated a common ancestral origin of the\ud mutation, which originated about 1,550 years ago. The\ud mutation is currently classified as having an uncertain clinical\ud significance. Clinical features, tissue analysis and co-segregation\ud with disease strongly support the hypothesis that the\ud MLH1 c.2252_2253delAA mutation has a pathogenic effec

Pancreatic Cancer in Lynch Syndrome Patients

“…Cajal et al 37 identified a mutation n c.2252_2253delAA, p.Lys751Serfs*3 en el exón 19 del gen MLH1 in an Italian patient. This mutation was previously noted as pathogenic in Korea, Denmark, United Kingdom, Germany and Australia and described by Borrelli et al 38 in a MLH1 mutation (c2253_2253delAA) that co-segregates with LS cancer in 11 unrelated families. All families had at least one colon cancer diagnosed before age of 50 and one case with multiple LS related tumors.…”

Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome

“…Through segregation investigation, computational analyses, mRNA processing and stability assays and protein expression experiments, Borras et al were able to confirm that two MLH1 founder changes from Spain, a splice variant (c.306+5G>A) and a missense variant (c.1865T>A), were pathogenic and the cause of the disease in carrier families (33). In Italy, the mutation c.2252_2253del significantly increased the risk of pancreatic tumors compared with other MLH1 mutations (82). In Tenerife Island, the MSH2 c.2063T>G missense variant was considered pathogenic because of the switch of polarity of the aminoacid change (p.Met688Arg) and the conservation between species of the affected residue, which belongs to an important functional domain of the protein (79).…”

MIA PaCa-2 and PANC-1 – pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors

“…Furthermore, the risk of developing a pancreatic tumor is 8.6 times more in patients with Lynch syndrome compared to the general population 18 . In these patients, a c.2252_2253delAA MLH1 mutation associated with an increased risk of pancreatic tumors 19 was found, and another in the MSH2 gene associated with an intraductal papillary mucinous neoplasm 20 was also discovered.…”