A new mutation in the hMSH2 gene in a Spanish Lynch syndrome family

Clinical Genetics Unit, University Clinic of Navarra, Pamplona, Navarra, Spain.
Clinical and Translational Oncology (Impact Factor: 2.08). 12/2010; 12(12):849-51. DOI: 10.1007/s12094-010-0596-3
Source: PubMed
ABSTRACT
We report a new germline mutation in exon 13 of the hMSH2 gene (c.2081T>C; F694S) in a patient diagnosed with colorectal carcinoma. The patient's family fulfilled the clinical criteria of the Bethesda guidelines for Lynch syndrome. The segregation analysis determined the presence of the mutation in the proband's mother (breast cancer younger than 40 years old) and in two healthy daughters. The mutation was not present in 116 normal controls screened. The medical implications for the carrier relatives are discussed.

Full-text

Available from: Iosu Sola, Mar 13, 2016
Abstract We report a new germline mutation in exon 13
of the hMSH2 gene (c.2081T>C; F694S) in a patient di-
agnosed with colorectal carcinoma. The patient’s family
fulfi lled the clinical criteria of the Bethesda guidelines for
Lynch syndrome. The segregation analysis determined the
presence of the mutation in the proband’s mother (breast
cancer younger than 40 years old) and in two healthy
daughters. The mutation was not present in 116 normal
controls screened. The medical implications for the carrier
relatives are discussed.
Keywords MSH2 · Lynch syndrome · Breast cancer ·
Spanish · Colon cancer
Case and family report
The proband was a 57-year-old Caucasian man from the north of
Spain (II.1 in Fig. 1), who had been diagnosed with a colorectal car-
cinoma (CCR) at the University Clinic of Navarra in 1996 when he
was 44 years old. After a right hemicolectomy, pathological exami-
nations revealed a moderately differentiated colon adenocarcinoma,
Dukes B2 (pT3N0M0). The immunohistochemical study reported the
absence of MSH2 and MSH6 proteins in the tumour sample (Fig. 2).
When the clinical and pathological antecedents of the family were
recorded, a familiar aggregation compatible with the clinical criteria
of Bethesda guidelines for Lynch syndrome was evident (Fig. 1).
Written informed consent was obtained from all the individuals
under study. A peripheral blood sample was obtained from individu-
als I.2, II.1, III.1, III.2 and III.3, and genomic DNA was extracted us-
ing the DNA Isolation Kit I from MagNa Pure LC (Roche, Barcelona,
Spain) according to the manufacturer’s instructions. All exons and in-
R. Zárate () · A. Patiño-García · J. García-Foncillas
Clinical Genetics Unit
University Clinic of Navarra (CUN)
Avda. Pío XII, 36
ES-31008 Pamplona, Navarra, Spain
e-mail: rzarate@unav.es
A. Patiño-García
Laboratory of Pediatrics
Departament of Pediatrics
University Clinic of Navarra (CUN)
Pamplona, Navarra, Spain
J. Sola
Department of Pathology
University Clinic of Navarra (CUN)
Pamplona, Navarra, Spain
J. García-Foncillas
Department of Oncology
University Clinic of Navarra (CUN)
Pamplona, Navarra, Spain
Clin Transl Oncol (2010) 12:
849-851
DOI 10.1007/s12094-010-0596-3
CASE REPORTS
A new mutation in the hMSH2 gene in a Spanish Lynch
syndrome family
Ruth Zárate · Ana Patiño-García · Jesús Sola · Jesús García-Foncillas
Received: 12 August 2010 / Accepted: 18 September 2010
Fig. 1 Family tree with the index case indicated by an arrow
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850
Clin Transl Oncol (2010) 12:849-851
tronic splicing regions of the hMSH2 gene (NG_007110.1) were am-
plifi ed by PCR and subsequently sequenced with an ABI PRISM™
3130XL DNA Sequencer (Applied Biosystems, Madrid, Spain).
A missense mutation (a T-to-C transition) was detected in exon 13
of hMSH2 (c.2081T>C/p.F694S) of the index case (Fig. 3). To the best
of our knowledge, this alteration has not been previously described in
the literature (HGMD database: http://www.hgmd.cf.ac.uk/ac/index.
php; MMR Gene Unclassifi ed Variants Database: www.mmruv.info).
We subsequently performed a segregation analysis and deter-
mined the presence of the F694S mutation in the proband’s mother
Fig. 2 Immunostaining for the MMR proteins. Pink arrows show tumour cells with missing MSH2 and MSH6 expression. Interstitial lympho-
cytes are stained as a positive control (orange arrows)
Fig. 3 Chromatograms showing the wild-type
(upper panel) and mutated (lower panel)
MSH2 genomic sequence
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Clin Transl Oncol (2010) 12:849-851
851
(I.2, breast cancer younger than 40 years) and in two daughters (III.2
and III.3). This fi nding may have important consequences for the fam-
ily members since they might be at risk of colorectal cancer or other
extra-colonic tumours. Individuals III.2 and III.3 should undergo a
colonoscopy every two years from 10 years before the proband’s age
at cancer diagnosis [1]. In the same way, and regarding the family his-
tory of breast cancer, mammography could be recommended.
There is an entry in the International Society for Gastrointestinal
Hereditary Tumours database (www.insight-group.org) correspond-
ing to a different missense mutation affecting the same codon:
c.2080T>C, pF694L. This mutation, reported by Murata and co-work-
ers [2], was detected in a sporadic breast cancer patient whose tumour
showed instability in one of the microsatellite markers analysed and a
strong protein MSH2 expression. This fi nding, together with the mu-
tation reported herein, also detected in a breast cancer patient (I.2),
might indicate that alterations in this codon of the MSH2 gene might
confer an increased susceptibility to breast cancer in Lynch families.
Evaluation of the c.2081 T>C mutation in a population
control
Exon 13 of the hMSH2 gene was PCR-amplifi ed and se-
quenced in 116 randomly selected controls. All the control
chromosomes carried the wild-type sequence at this codon
and therefore the maximum frequency of the mutant allele
would be 0.4%. We did not detect any other changes in the
exon 13 sequence in the control individuals.
Acknowledgements We are grateful to all the family members for
their full cooperation during this study. We thank Dr. M. Herráiz for
critical reading of this case report.
Confl ict of interest The authors declare that they have no confl ict of
interest relating to the publication of this manuscript.
References
1. Vasen HF, Möslein G, Alonso A et al (2007)
Guidelines for the clinical management of Lynch
syndrome (hereditary non-polyposis cancer). J
Med Genet 44:353–362
2. Murata H, Khattar NH, Kang Y et al (2002) Ge-
netic and epigenetic modifi cation of mismatch re-
pair genes hMSH2 and hMLH1 in sporadic breast
cancer with microsatellite instability. Oncogene
21:5696–5703
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  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Breast cancer is the most common cancer in women, but its pathogenesis is still unclear. Microsatellite instability (MSI) has been identified in breast cancer cells, suggesting an association with mismatch repair defects. To test this hypothesis, we investigated MSI, protein expression of hMSH2 and hMLH1, as well as genetic and epigenetic modifications of these two genes in 32 sporadic breast tumors. MSI was identified in 15 cases. Immunohistochemistry analysis revealed that all MSI cases but one had lower than normal expression of hMSH2 (nine cases), hMLH1 (12 cases), or both (seven cases). In tumors with MSI, both genetic and epigenetic modifications of these mismatch repair genes were also identified. Eight cases harbored mutations or polymorphisms in hMSH2 and hMLH1, and 10 exhibited hypermethylation in the promoter region of hMLH1. These results suggest that both genetic and epigenetic alterations of hMSH2 and especially of hMLH1 contribute to genomic instability and tumorigenesis in sporadic breast cancer.
    Preview · Article · Sep 2002 · Oncogene
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.
    Full-text · Article · Jul 2007 · Journal of Medical Genetics
  • Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). . 2007. J Med Genet 44 353-362.