Advertisement

Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 597–602 | Cite as

Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer

  • Berta CamposEmail author
  • Judith Balmaña
  • Josep Gardenyes
  • Irene Valenzuela
  • Oscar Abad
  • Pere Fàbregas
  • Víctor Volpini
  • Orland Díez
Brief Report

Abstract

Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are café-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed.

Keywords

NF1 BRCA1 Neurofibromatosis 1 Early-onset breast cancer Genetic counseling 

Notes

Acknowledgments

We thank the proband and her family for their participation in this study. All research carried out for this study complies with the current laws of Spain.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1. Am J Epidemiol 151(1):33–40PubMedCrossRefGoogle Scholar
  2. 2.
    Brems H, Beert E, de Ravel T, Legius E (2009) Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol 10(5):508–515PubMedCrossRefGoogle Scholar
  3. 3.
    Sorensen SA, Mulvihill JJ, Nielsen A (1986) Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 314(16):1010–1015PubMedCrossRefGoogle Scholar
  4. 4.
    Zoller ME, Rembeck B, Oden A, Samuelsson M, Angervall L (1997) Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 79(11):2125–2131PubMedCrossRefGoogle Scholar
  5. 5.
    Korf BR (2000) Malignancy in neurofibromatosis type 1. Oncologist 5(6):477–485PubMedCrossRefGoogle Scholar
  6. 6.
    Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D (2006) A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer 95(2):233–238PubMedCrossRefGoogle Scholar
  7. 7.
    Yohay K (2009) Neurofibromatosis type 1 and associated malignancies. Curr Neurol Neurosci Rep 9(3):247–253PubMedCrossRefGoogle Scholar
  8. 8.
    Easton DF, Ford D, Bishop DT (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56(1):265–271PubMedGoogle Scholar
  9. 9.
    Whittemore AS, Gong G, Itnyre J (1997) Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer. Am J Hum Genet 60(3):496–504PubMedGoogle Scholar
  10. 10.
    Yaegashi S, Sachse R, Ohuchi N, Mori S, Sekiya T (1995) Low incidence of a nucleotide sequence alteration of the neurofibromatosis 2 gene in human breast cancers. Jpn J Cancer Res 86(10):929–933PubMedCrossRefGoogle Scholar
  11. 11.
    Ogata H, Sato H, Takatsuka J, De Luca LM (2001) Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras. Cancer Lett 172(2):159–164PubMedCrossRefGoogle Scholar
  12. 12.
    Nakamura M, Tangoku A, Kusanagi H, Oka M, Suzuki T (1998) Breast cancer associated with Recklinghausen’s disease: report of a case. Nihon Geka Hokan 67(1):3–9PubMedGoogle Scholar
  13. 13.
    el-Zawahry MD, Farid M, Abd el-Latif A, Horeia H, el-Gindy M, Twakal G (1989) Breast lesions in generalized neurofibromatosis: breast cancer and cystosarcoma phylloides. Neurofibromatosis 2(2):121–124PubMedGoogle Scholar
  14. 14.
    Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95 % of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 15(6):541–555PubMedCrossRefGoogle Scholar
  15. 15.
    den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15(1):7–12CrossRefGoogle Scholar
  16. 16.
    Rasmussen SA, Yang Q, Friedman JM (2001) Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet 68(5):1110–1118PubMedCrossRefGoogle Scholar
  17. 17.
    Murayama Y, Yamamoto Y, Shimojima N, Takahara T, Kikuchi K, Iida S, Kondo Y (1999) Ti breast cancer associated with Von Recklinghausen’s neurofibromatosis. Breast Cancer 6(3):227–230CrossRefGoogle Scholar
  18. 18.
    Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, Evans DG (2007) Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 44(8):481–484PubMedCrossRefGoogle Scholar
  19. 19.
    Ceccaroni M, Genuardi M, Legge F, Lucci-Cordisco E, Carrara S, D’Amico F, Greggi S, Scambia G (2002) BRCA1-related malignancies in a family presenting with von Recklinghausen’s disease. Gynecol Oncol 86(3):375–378PubMedCrossRefGoogle Scholar
  20. 20.
    Guran S, Safali M (2005) A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer. Cancer Genet Cytogenet 156(1):86–88PubMedCrossRefGoogle Scholar
  21. 21.
    Salemis NS, Nakos G, Sambaziotis D, Gourgiotis S (2010) Breast cancer associated with type 1 neurofibromatosis. Breast Cancer 17(4):306–309PubMedCrossRefGoogle Scholar
  22. 22.
    Madanikia SA, Bergner A, Ye X, Blakeley JO (2012) Increased risk of breast cancer in women with NF1. Am J Med Genet A 158A(12):3056–3060PubMedCrossRefGoogle Scholar
  23. 23.
    Wang X, Levin AM, Smolinski SE, Vigneau FD, Levin NK, Tainsky MA (2012) Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area. Am J Med Genet A 158A(12):3061–3064PubMedCrossRefGoogle Scholar
  24. 24.
    Wilson CH, Griffith CD, Shrimankar J, Douglas F (2004) Gynaecomastia, neurofibromatosis and breast cancer. Breast 13(1):77–79PubMedCrossRefGoogle Scholar
  25. 25.
    Bradbury AR, Olopade OI (2007) Genetic susceptibility to breast cancer. Rev Endocr Metab Disord 8(3):255–267PubMedCrossRefGoogle Scholar
  26. 26.
    Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JF Jr, Li FP (1991) Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51(22):6094–6097PubMedGoogle Scholar
  27. 27.
    Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ, Keller JJ, Westerman AM, Scott RJ, Lim W, Trimbath JD, Giardiello FM, Gruber SB, Offerhaus GJ, de Rooij FW, Wilson JH, Hansmann A, Moslein G, Royer-Pokora B, Vogel T, Phillips RK, Spigelman AD, Houlston RS (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12(10):3209–3215PubMedCrossRefGoogle Scholar
  28. 28.
    Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D (2007) Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297(21):2360–2372PubMedCrossRefGoogle Scholar
  29. 29.
    Bogdanova N, Feshchenko S, Schurmann P, Waltes R, Wieland B, Hillemanns P, Rogov YI, Dammann O, Bremer M, Karstens JH, Sohn C, Varon R, Dork T (2008) Nijmegen breakage syndrome mutations and risk of breast cancer. Int J Cancer 122(4):802–806PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Berta Campos
    • 1
    Email author
  • Judith Balmaña
    • 2
  • Josep Gardenyes
    • 1
  • Irene Valenzuela
    • 3
  • Oscar Abad
    • 1
  • Pere Fàbregas
    • 1
  • Víctor Volpini
    • 1
  • Orland Díez
    • 4
  1. 1.Center for Molecular Genetic Diagnosis (CDGM)—IDIBELLL’Hospitalet de LlobregatSpain
  2. 2.High Risk and Cancer Prevention Unit, Medical Oncology DepartmentUniversity Hospital Vall HebronBarcelonaSpain
  3. 3.Genetics UnitUniversity Hospital Vall d’HebronBarcelonaSpain
  4. 4.Oncogenetics LaboratoryUniversity Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de BarcelonaBarcelonaSpain

Personalised recommendations