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

Iolanda Borelli, Guido C. Casalis Cavalchini, Serena Del Peschio, Monica Micheletti, Tiziana Venesio, Ivana Sarotto, Anna Allavena, Luisa Delsedime, Marco A. Barberis, Giorgia Mandrile, Paola Berchialla, Paola Ogliara, Cecilia Bracco, Barbara Pasini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)401-413
Number of pages13
JournalFamilial Cancer
Volume13
Issue number3
DOIs
Publication statusPublished - Sep 1 2014

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Hereditary Nonpolyposis Colorectal Neoplasms
Italy
Mutation
Neoplasms
Microsatellite Instability
Founder Effect
DNA Mismatch Repair
Dimerization
Colonic Neoplasms
Haplotypes
Staining and Labeling
Phenotype

Keywords

  • Focal immunohistochemical expression
  • Founder effect
  • Lynch syndrome
  • MLH1 mutations
  • MLH1-PMS2 dimerization

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Oncology
  • Genetics(clinical)
  • Medicine(all)

Cite this

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

In: Familial Cancer, Vol. 13, No. 3, 01.09.2014, p. 401-413.

Research output: Contribution to journalArticle

Borelli, I, Casalis Cavalchini, GC, Del Peschio, S, Micheletti, M, Venesio, T, Sarotto, I, Allavena, A, Delsedime, L, Barberis, MA, Mandrile, G, Berchialla, P, Ogliara, P, Bracco, C & Pasini, B 2014, 'A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns', Familial Cancer, vol. 13, no. 3, pp. 401-413. https://doi.org/10.1007/s10689-014-9726-3
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. / A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns. In: Familial Cancer. 2014 ; Vol. 13, No. 3. pp. 401-413.
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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.",
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T1 - A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

AU - Borelli, Iolanda

AU - Casalis Cavalchini, Guido C.

AU - Del Peschio, Serena

AU - Micheletti, Monica

AU - Venesio, Tiziana

AU - Sarotto, Ivana

AU - Allavena, Anna

AU - Delsedime, Luisa

AU - Barberis, Marco A.

AU - Mandrile, Giorgia

AU - Berchialla, Paola

AU - Ogliara, Paola

AU - Bracco, Cecilia

AU - Pasini, Barbara

PY - 2014/9/1

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N2 - 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.

AB - 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.

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