Abstract
Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.
This is a preview of subscription content, log in via an institution to check access.
References
de Winter JP, Joenje H (2009) The genetic and molecular basis of Fanconi anemia. Mutat Res 668(1–2):11–19
Kim Y, Lach FP, Desetty R, Hanenberg H, Auerbach AD, Smogorzewska A (2010) Mutations of the SLX4 gene in Fanconi anemia. Nat Genet 43(2):142–146
Stoepker C, Hain K, Schuster B et al (2010) SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet 43(2):138–141
Vaz F, Hanenberg H, Schuster B et al (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409
Rosenberg PS, Alter BP, Ebell W (2008) Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 93(4):511–517
Rosenberg PS, Greene MH, Alter BP (2003) Cancer incidence in persons with Fanconi anemia. Blood 101(3):822–826
Tischkowitz M, Dokal I (2004) Fanconi anaemia and leukaemia—clinical and molecular aspects. Br J Haematol 126(2):176–191
Wooster R, Neuhausen SL, Mangion J et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science (New York, NY 265(5181): 2088–2090
Rahman N, Seal S, Thompson D et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167
Meindl A, Hellebrand H, Wiek C et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414
Rafnar T, Gudbjartsson DF, Sulem P et al (2011) Mutations in BRIP1 confer high risk of ovarian cancer. Nat genet 43(11):1104–1107.doi:10.1038/ng.955 ng.955
Foulkes WD (2008) Inherited susceptibility to common cancers. N Engl J Med 359(20):2143–2153. doi:10.1056/NEJMra0802968
Ameziane N, Errami A, Leveille F et al (2008) Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat 29(1):159–166
Borriello A, Locasciulli A, Bianco AM et al (2007) A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia. Leukemia 21(1):72–78
Kalb R, Neveling K, Hoehn H et al (2007) Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Am J Hum Genet 80(5):895–910
LeBron C, Pal P, Brait M et al (2011) Genome-wide analysis of genetic alterations in testicular primary seminoma using high resolution single nucleotide polymorphism arrays. Genomics 97(6):341–349
Alter BP, Rosenberg PS, Brody LC (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44(1):1–9
Rischewski JR, Clausen H, Leber V et al (2000) A heterozygous frameshift mutation in the Fanconi anemia C gene in familial T-ALL and secondary malignancy. Klin Padiatr 212(4):174–176
Holzel M, van Diest PJ, Bier P et al (2003) FANCD2 protein is expressed in proliferating cells of human tissues that are cancer-prone in Fanconi anaemia. J Pathol 201(2):198–203
Lin YJ, Lan YC, Wan L et al (2010) The NBS1 genetic polymorphisms and the risk of the systemic lupus erythematosus in Taiwanese patients. J Clin Immunol 30(5):643–648
Davies RC, Pettijohn K, Fike F et al (2011) DNA double strand break repair is defective in pediatric systemic lupus erythematosus. Arthr Rheum
Acknowledgments
We are grateful to Gary Ashton for excellent immunohistochemistry. Grant support: CRUK Clinician Scientist Fellowship to SM. ADW and SM are supported by LLR, UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Smetsers, S., Muter, J., Bristow, C. et al. Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma. Familial Cancer 11, 661–665 (2012). https://doi.org/10.1007/s10689-012-9553-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-012-9553-3