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Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria

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Abstract

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

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Abbreviations

CMMRD:

Constitutional mismatch repair deficiency

CRC:

Colorectal cancer

gMSI:

Germline microsatellite instability

LR:

Likelihood ratio

LS:

Lynch syndrome

MMR:

Mismatch repair

MSI:

Microsatellite instability

VUS:

Variant of unknown significance

References

  1. Kunkel TA, Erie DA (2015) Eukaryotic mismatch repair in relation to DNA replication. Annu Rev Genet 49:291–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Adam R, Spier I, Zhao B et al (2016) Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet 99(2):337–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vasen HF, Tomlinson I, Castells A (2015) Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol 12(2):88–97

    Article  PubMed  Google Scholar 

  4. Wimmer K, Kratz CP, Vasen HF et al (2014) Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet 51(6):355–365

    Article  CAS  PubMed  Google Scholar 

  5. Sijmons RH, Hofstra RM (2016) Review: clinical aspects of hereditary DNA Mismatch repair gene mutations. DNA Repair 38:155–162

    Article  CAS  PubMed  Google Scholar 

  6. Kets CM, Hoogerbrugge N, van Krieken JH, Goossens M, Brunner HG, Ligtenberg MJ (2009) Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A > G of MSH2. Eur J Hum Genet 17(2):159–164

    Article  CAS  PubMed  Google Scholar 

  7. Aronson M, Gallinger S, Cohen Z et al (2016) Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium. Am J Gastroenterol 111(2):275–284

    Article  CAS  PubMed  Google Scholar 

  8. Li L, Hamel N, Baker K et al (2015) A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype. J Med Genet 52(5):348–352

    Article  PubMed  Google Scholar 

  9. Bodas A, Perez-Segura P, Maluenda C, Caldes T, Olivera E, Diaz-Rubio E (2008) Lynch syndrome in a 15-year-old boy. Eur J Pediatr 167(10):1213–1215

    Article  CAS  PubMed  Google Scholar 

  10. Durno CA, Sherman PM, Aronson M et al (2015) Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur J Cancer 51(8):977–983

    Article  CAS  PubMed  Google Scholar 

  11. Herkert JC, Niessen RC, Olderode-Berends MJ et al (2011) Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines. Eur J Cancer 47(7):965–982

    Article  CAS  PubMed  Google Scholar 

  12. Will O, Carvajal-Carmona LG, Gorman P et al (2007) Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer. Gastroenterology 132(2):527–530

    Article  CAS  PubMed  Google Scholar 

  13. Ingham D, Diggle CP, Berry I et al (2013) Simple detection of germline microsatellite instability for diagnosis of constitutional mismatch repair cancer syndrome. Hum Mutat 34(6):847–852

    Article  CAS  PubMed  Google Scholar 

  14. Borras E, Pineda M, Cadinanos J et al (2013) Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet 50(8):552–563

    Article  CAS  PubMed  Google Scholar 

  15. Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN (2009) EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 11(1):42–65

    Article  PubMed  PubMed Central  Google Scholar 

  16. Moller P, Seppala T, Bernstein I et al. (2015) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 66:464–472

    Article  PubMed  PubMed Central  Google Scholar 

  17. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW (2015) ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110(2):223–262 (quiz 63)

    Article  PubMed  PubMed Central  Google Scholar 

  18. Clendenning M, Hampel H, LaJeunesse J et al (2006) Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 27(5):490–495

    Article  CAS  PubMed  Google Scholar 

  19. Vaughn CP, Robles J, Swensen JJ et al (2010) Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum Mutat 31(5):588–593

    CAS  PubMed  Google Scholar 

  20. Ganster C, Wernstedt A, Kehrer-Sawatzki H et al (2010) Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event. Hum Mutat 31(5):552–560

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Thompson BA, Spurdle AB, Plazzer JP et al (2014) Application of a 5-tiered scheme for standardized classification of 2360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46(2):107–115

    Article  CAS  PubMed  Google Scholar 

  22. Heinen CD (2016) Mismatch repair defects and Lynch syndrome: the role of the basic scientist in the battle against cancer. DNA Repair 38:127–134

    Article  CAS  PubMed  Google Scholar 

  23. Thompson BA, Goldgar DE, Paterson C et al (2013) A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. Hum Mutat 34(1):200–209

    Article  CAS  PubMed  Google Scholar 

  24. ten Broeke SW, Brohet RM, Tops CM et al (2015) Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol 33(4):319–325

    Article  PubMed  Google Scholar 

  25. Plon SE, Eccles DM, Easton D et al (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29(11):1282–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Etzler J, Peyrl A, Zatkova A et al (2008) RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Hum Mutat 29(2):299–305

    Article  CAS  PubMed  Google Scholar 

  27. Plotz G, Welsch C, Giron-Monzon L et al (2006) Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair. Nucleic Acids Res 34(22):6574–6586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brea-Fernandez AJ, Cameselle-Teijeiro JM, Alenda C et al (2014) High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families. Clin Genet 85(6):583–588

    Article  CAS  PubMed  Google Scholar 

  29. van der Klift HM, Tops CM, Bik EC et al (2010) Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. Hum Mutat 31(5):578–587

    PubMed  Google Scholar 

  30. van der Klift HM, Mensenkamp AR, Drost M et al. (2016) Comprehensive mutation analysis of PMS2 in a large cohort of probands suspected of lynch syndrome or constitutional mismatch repair deficiency syndrome. Hum Mutat 37:1162–1179

    Article  PubMed  Google Scholar 

  31. Shah KN (2010) The diagnostic and clinical significance of cafe-au-lait macules. Pediatr Clin N Am 57(5): 1131–1153

    Article  Google Scholar 

  32. Bodo S, Colas C, Buhard O et al (2015) Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents. Gastroenterology 149(4):1017–1029

    Article  PubMed  Google Scholar 

  33. van der Klift HM, Jansen AM, van der Steenstraten N et al (2015) Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. Mol Genet Genom Med 3(4):327–345

    Article  Google Scholar 

  34. Drost M, Koppejan H, de Wind N (2013) Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. Hum Mutat 34(11):1477–1480

    Article  CAS  PubMed  Google Scholar 

  35. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424

    Article  PubMed  PubMed Central  Google Scholar 

  36. Goodenberger ML, Thomas BC, Riegert-Johnson D et al (2016) PMS2 monoallelic mutation carriers: the known unknown. Genet Med 18(1):13–19

    Article  CAS  PubMed  Google Scholar 

  37. ten Broeke SW, Nielsen M (2015) A PMS2-specific colorectal surveillance guideline. Genet Med 17(8):684

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds- a way to build Europe-(SAF2012-33636 and SAF2015-68016); the Scientific Foundation Asociación Española Contra el Cáncer; the Government of Catalonia (2014SGR338), Fundación Mutua Madrileña (AP114252013) and Red Temática de Investigación Cooperativa en Cáncer (RTICC RD12/0036/0031 and RD12/0036/0008). MG-A was supported by grants AP114252013, RD12/0036/0031 and the Scientific Foundation Asociación Española Contra el Cáncer. BAT is an NHMRC Early Career Fellow. We are indebted to the patients and the members of the Hereditary Cancer Genetic Counseling Units. We also thank Benjamin Puliafito for the English revision of the manuscript and valuable remarks.

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Correspondence to Gabriel Capellá.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Marta Pineda and Gabriel Capellá have contributed equally to this work and share senior authorship.

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González-Acosta, M., del Valle, J., Navarro, M. et al. Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria. Familial Cancer 16, 501–507 (2017). https://doi.org/10.1007/s10689-017-9981-1

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