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Co-Occurrence of Nonsense Mutations in MSH6 and MSH2 in Lynch Syndrome Families Evidencing That Not All Truncating Mutations Are Equal

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Co-Occurrence of Nonsense Mutations in MSH6 and MSH2 in Lynch Syndrome Families Evidencing That Not All Truncating Mutations Are Equal Journal of Human Genetics (2016) 61, 151–156 & 2016 The Japan Society of Human Genetics All rights reserved 1434-5161/16 www.nature.com/jhg ORIGINAL ARTICLE Co-occurrence of nonsense mutations in MSH6 and MSH2 in Lynch syndrome families evidencing that not all truncating mutations are equal Carla Pinto1, Manuela Pinheiro1, Ana Peixoto1, Catarina Santos1, Isabel Veiga1, Patrícia Rocha1, Pedro Pinto1, Paula Lopes2, Manuela Baptista3, Rui Henrique2,4 and Manuel R Teixeira1,4 The majority of pathogenic mismatch repair (MMR) gene mutations detected in Lynch syndrome patients are truncating (frameshift or nonsense). However, the classification of terminal truncating mutations is sometimes difficult and predictive testing based on non-deleterious variants can have very serious consequences. Here, we report eight probands that have two germline nonsense mutations, namely MSH6 c.1030C4T, p.(Gln344Ter) and MSH2 c.2785C4T, p.(Arg929Ter), and one additional patient who presented only the MSH2 mutation previously reported as deleterious. The novel MSH6 truncating mutation was classified as deleterious, as it is predicted to encode a protein with loss of 1017 amino acid residues. The MSH2 mutation, which is expected to encode a protein lacking six amino acid residues, was considered a variant of unknown significance. Five tumors of the eight double-mutant individuals had normal MSH2 expression, whereas MSH6 immunoexpression was lost in all evaluable cases. None of the variants were detected in normal controls or associated with other MMR germline mutations in our series. This study emphasizes that not all truncating mutations are equal and that one must be cautious in the interpretation of the presumed deleterious effect of terminal frameshift or nonsense mutations. Journal of Human Genetics (2016) 61, 151–156; doi:10.1038/jhg.2015.124; published online 8 October 2015 INTRODUCTION Lynch syndrome families, whereas mutations in the MSH6 and Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal PMS2 genes appear to be more associated with atypical Lynch Cancer (MIM# 120435), is the most common hereditary colon cancer syndrome.8–10 As molecular characterization of Lynch syndrome was syndrome, representing 2–5% of all colorectal cancer (CRC), includ- established, the identification of gene carriers has become a critical 1–3 ing a large proportion of those with a young age of diagnosis. issue with important clinical implications for cancer surveillance, MMR MLH1 Germline mutations in mismatch repair ( )genes( , MIM# incidence and mortality.11 The identification of patients with Lynch MSH2 MSH6 PMS2 120436; , MIM# 609309; , MIM# 600678; and , syndrome can be facilitated in populations with founder mutations MIM# 600259) are the major causes of Lynch syndrome, which is a by targeting the mutational analysis to specific gene regions as a highly penetrant autosomal dominant disease characterized by first step, improving the cost effectiveness of the genetic testing increased risk for CRC and extracolonic tumors of the endometrium, strategy.12–14 stomach, small bowel, ureter, renal pelvis, ovary and hepatobiliary The majority of MMR gene variants that are detected in Lynch tract.4 The vast majority of Lynch syndrome-associated tumors syndrome patients are truncating mutations, which are generally presents microsatellite instability due to their DNA MMR deficiency. classified as pathogenic. However, there are examples in the literature In addition, microsatellite instability tumors can be identified by that terminal nonsense mutations may be polymorphisms with no abnormal MMR immunohistochemical staining as the MMR gene major functional consequences for the encoding protein, as is the case mutated in the germline usually loses the wild-type allele in the of the terminal BRCA2 mutation c.9976A4T, p.(Lys3326Ter).15 The tumor cells.5 fi The detection of pathogenic MMR mutations in patients suspected classi cation of terminal truncating mutations may therefore be fi of having Lynch syndrome confirms the diagnosis and allows genetic dif cult and could have very serious consequences for cancer families counseling and predictive testing in their relatives.6 About 90% of if a non-deleterious variant is used for predictive genetic testing. germline mutations in Lynch syndrome are found in MLH1 and We here present eight families that have two germline nonsense MSH2,7%inMSH6 and 1% in PMS2.7 The germline mutations in mutations, one novel mutation in MSH6 exon 4 and a MSH2 exon 16 MLH1 or MSH2 are usually associated with clinically recognizable mutation previously reported as deleterious. 1Department of Genetics, Portuguese Oncology Institute, Porto, Portugal; 2Department of Pathology, Portuguese Oncology Institute, Porto, Portugal; 3Department of Surgery, São João Hospital, Porto, Portugal and 4Institute of Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal Correspondence: Professor MR Teixeira, Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, S/N, Porto 4200-072, Portugal. E-mail: [email protected] Received 25 June 2015; revised 30 July 2015; accepted 11 September 2015; published online 8 October 2015 Co-occurrence of nonsense mutations CPintoet al 152 MATERIALS AND METHODS MMR immunohistochemical analysis Patients, samples and DNA extraction Assessment of MLH1, MSH2, MSH6 and PMS2 immunoexpression was This study includes eight Lynch syndrome families presenting two concomitant performed as previously described in the eight tumors from the patients truncating mutations in the MSH6 and MSH2 genes, from a total series of 114 harboring the two truncating mutations in MSH2 and MSH6 (the tumor from families with pathogenic MLH1, MSH2, MSH6 or PMS2 germline mutations the patient with isolated MSH2 mutation was not available).20 (data not shown). Seven of these index patients were identified by routine genetic diagnosis during the period of 1997–2014 at the Genetics Department Microsatellite typing and haplotype analysis of the Portuguese Oncology Institute, Porto, Portugal, after genetic counseling A total of 9 probands and 16 family members were genotyped for a subset of 10 and informed consent. The remaining index patient was initially sent to us as a microsatellite markers (D2S391, D2S2227, Clen33, Clen30, Clen29, D2S2156, familial case belonging to a family with the MSH2 mutation identified in D2S123, Clen43, Clen44 and D2S378) flanking MSH6 and MSH2. The physical France. In addition to these eight families, we also identified one family that distances of the genetic markers were derived from the National Center for only presented the MSH2 germline mutation. Seven families were followed up Biotechnology Information (NCBI) Map Viewer (http://www.ncbi.nlm.nih.gov/ at the Portuguese Oncology Institute and two at São João Hospital. Three projects/mapview/). The primer sequences for amplification of the markers families fulfilled the Amsterdam criteria, whereas the remaining presented the D2S391, D2S123 and D2S378 were derived from the Human Genome database; Bethesda criteria for genetic testing (Table 1 and Figure 1).16,17 After written primers for markers D2S2227 and D2S2156 were designed using the online informed consent, DNA was isolated from peripheral blood samples from the Primer-BLAST tool (http://www.ncbi.nlm.nih.gov/tools/primer-blast/), and nine index individuals and subsequently from 16 family members, using markers Clen33, Clen30, Clen29, Clen43 and Clen44 were derived from standard procedures. The geographic origin of these families was inferred from Clendenning and co-workers.21 All 10 markers were assayed by PCR using the birthplace of the oldest carrier or of the oldest affected family member most fluorescently end-labeled primers. PCR products were run on an ABI PRISM likely to be a carrier. 310 Genetic Analyzer together with the fluorescence-labeled DNA fragment size standard TAMRA (Applied Biosystems). Haplotype construction was Screening for MMR germline alterations performed manually based on the genotypes obtained from index cases and Genomic DNA from the eight patients was screened for MMR germline family members. mutations. MSH2 and MSH6 coding exons and flanking regions were studied by denaturing gradient gel electrophoresis using primers and conditions as Statistical analysis described by Wu and co-workers and Ingeny (Goes, The Netherlands) and/or Comparison of mean age of CRC diagnosis was performed by Mann–Whitney by direct sequencing in an ABI PRISM 3500 automatic sequencer using Big Dye test and P-values o0.05 were considered statistically significant. Terminator Chemistry (Applied Biosystems, Foster City, CA, USA), according to the manufacturer’srecommendations.18 Whenever necessary, MSH6 exon 7 RESULTS was re-sequenced using a different set of primers to exclude or confirm the Mutation analyses presence of a polymorphism at the initial primer annealing site.19 MSH2 and Analysis of the constitutional DNA by denaturing gradient gel MSH6 exonic rearrangements were screened by multiplex ligation-dependent electrophoresis and Sanger sequencing in eight index cases initially probe amplification, according to the SALSA MLPA P003 MLH1/MSH2 and studied in Porto revealed, in seven of them, two germline mutations, P072 MSH6 kits (MRC-Holland, Amsterdam, The Netherlands) instructions. the MSH6 exon 4 c.1030C4T, p.(Gln344Ter) and the MSH2 exon The variants described are according to the Human Genome Variation Society 16 c.2785C4T, p.(Arg929Ter), whereas the eighth presented only
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