Abstract
Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive hereditary cancer condition, characterized by an exceptionally high risk of cancer, a propensity for childhood malignancies, and cutaneous features reminiscent of neurofibromatosis type 1 (NF1). We report on two sisters originally suspected of having CMMRD syndrome due to their history of colonic polyps and NF1 associated skin findings, both were subsequently found to have biallelic MSH6 mutations. After years of CMMRD syndrome follow-up, the proband was diagnosed with breast cancer at age 29, while her sister was diagnosed with a glioblastoma at age 27. Immunohistochemistry analysis on the breast tumor tissue revealed weak MSH6 protein staining. Exome sequencing revealed a hypermutated breast tumor and an ultra-hypermutated brain tumor. Multi-gene panel testing was also performed and revealed no additional mutations which might explain the proband’s early onset breast cancer. This is the first documented case of breast cancer in an individual with CMMRD syndrome. We summarize the evidence supporting the possible association between breast cancer and biallelic MMR mutations. Healthcare providers should be aware of this possible association and follow-up appropriately for suspicious breast findings. In addition, this case highlights the need for frequent central nervous system screenings due to rapid progression of brain tumors.
References
Vasen HFA, Ghorbanoghli Z, Bourdeaut F, Cabaret O, Caron O, Duval A, Entz-Werle N, Goldberg Y, Ilencikova D, Kratz CP, Lavoine N, Loeffen J, Menko FH, Muleris M, Sebille G, Colas C, Burkhardt B, Brugieres L, Wimmer K, on behalf of the EU-Consortium Care for CMMR-D (C4CMMR-D) (2014) Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). J Med Genet 51(5):283–293
Wimmer K, Kratz CP, Vasen HFA, Caron O, Colas C, Entz-Werle N, Gerdes AM, Goldberg Y, Ilencikova D, Muleris M, Duval A, Lavoine N, Ruiz-Ponte C, Slavc I, Burkhardt B, Brugieres L, on behalf of the EU-Consortium Care for CMMRD (C4CMMRD) (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
Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124(2):105–122
Wimmer K, Kratz CP (2010) Constitutional mismatch repair-deficiency syndrome. Haematologica 95(5):699–701
Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK, Alharbi M, Shamvil A, Ben-Shachar S, Mistry M, Constantini S, Dvir R, Qaddoumi I, Gallinger S, Lerner-Ellis J, Pollett A, Stephens D, Kelies S, Chao E, Malkin D, Bouffet E, Hawkins C, Tabori U (2014) Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer 50(5):987–996
Durno CA, Sherman PM, Aronson M, Malkin D, Hawkins C, Bakry D, Bouffet E, Gallinger S, Pollett A, Campbell B, Tabori U, International BMMRD Consortium (2015) Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur J Cancer 51(8):977–983
Hackman P, Tannergard P, Osei-Mensa S, Chen J, Kane MF, Kolodner R, Lambert B, Hellgren D, Lindblom A (1997) A human compound heterozygote for two MLH1 missense mutations. Nat Genet 17(2):135–136
Borg A, Isola J, Chen J, Rubio C, Johansson U, Werelius B, Lindblom A (2000) Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma. Int J Cancer 85(6):796–800
Jasperson KW, Samowitz WS, Burt RW (2011) Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Clin Genet 80(4):394–397
Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, Pollett A, Lipman T, Heidari A, Deshmukh S, Avitzur N, Meier B, Gerstung M, Hong Y, Merino DM, Ramakrishna M, Remke M, Arnold R, Panigrahi GB, Thakkar NP, Hodel KP, Henninger EE, Goksenin AY, Bakry D, Charames GS, Druker H, Lerner-Ellis J, Mistry M, Dvir R, Grant R, Elhasid R, Farah R, Taylor GP, Nathan PC, Alexander S, Ben-Shachar S, Ling SC, Gallinger S, Constantini S, Dirks P, Huang A, Scherer SW, Grundy RG, Durno C, Aronson M, Gartner A, Meyn MS, Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, Tabori U, Biallelic Mismatch Repair Deficiency Consortium (2015) Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 47(3):257–262
Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A (2017) Comprehensive analysis of hypermutation in human cancer. Cell 4(17):31142-X
Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A (1999) Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59(2):294–297
Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59(2):290–293
Ford JM (2012) Is breast cancer a part of Lynch syndrome? Breast Cancer Res 14(4):110
Verma L, Kane MF, Brassett C, Schmeits J, Evans DGR, Kolodner RD, Maher ER (1999) Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J Med Genet 36(9):678–682
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HFA, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96(4):261–268
Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, Buchanan DD, Clendenning M, Giles GG, Winship I, Macrae FA, Goldblatt J, Southey MC, Arnold J, Thibodeau SN, Gunawardena SR, Bapat B, Baron JA, Casey G, Gallinger S, Le Marchand L, Newcomb PA, Haile RW, Hopper JL, Jenkins MA (2012) Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30(9):958–964
Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, Schackert HK, Goergens H, von Knebel Doeberitz M, Goecke TO, Schmiegel W, Buettner R, Moeslein G, Letteboer TGW, Gomez Garcia E, Hes FJ, Hoogerbrugge N, Menko FH, van Os TAM, Sijmons RH, Wagner A, Kluijt I, Propping P, Vasen HFA (2012) Risks of less common cancers in proven mutation carriers with Lynch syndrome. J Clin Oncol 30(35):4409–4415
Win AK, Lindor NM, Jenkins MA (2013) Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res 15(2):R27
Beggs AD, Kousparos G, Hodgson SV (2013) Loss of mismatch repair protein expression in breast carcinoma in patients with Lynch Syndrome: report of two cases. Breast J 19(2):193–195
Harkness EF, Barrow E, Newton K, Green K, Clancy T, Lalloo F, Hill J, Evans DG (2015) Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J Med Genet 52(8):553–556
Acknowledgements
We would like to thank the family for their dedication to helping improve the lives of others affected by CMMRD syndrome through fundraising, advocacy, research and raising awareness.
Funding
The mutation burden analysis was funded through the SU2C Catalyst Research Grant and the Canadian Institute of Health Research Joint Israel-Canada Health Program.
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The authors declare that they have no conflict of interests.
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Obtained. This study was approved by the Mount Sinai Hospital Institutional Review Board. The family is enrolled in the Familial Gastrointestinal Cancer Registry (FGICR) and the International BMMRD Consortium.
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Bush, L., Aronson, M., Tabori, U. et al. Delineating a new feature of constitutional mismatch repair deficiency (CMMRD) syndrome: breast cancer. Familial Cancer 18, 105–108 (2019). https://doi.org/10.1007/s10689-018-0088-0
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DOI: https://doi.org/10.1007/s10689-018-0088-0