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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

Authors: Amanda Gonçalves Silva, Ingrid Petroni Ewald, Marina Sapienza, Manuela Pinheiro, Ana Peixoto, Amanda França de Nóbrega, Dirce M Carraro, Manuel R Teixeira, Patricia Ashton-Prolla, Maria Isabel W Achatz, Carla Rosenberg, Ana C V Krepischi

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype.

Methods

We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes.

Results

We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences.

Conclusion

This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.
Appendix
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Literature
1.
Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990, 250 (4985): 1233-1238. 10.1126/science.1978757.CrossRefPubMed
2.
Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW: A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988, 48 (18): 5358-5362.PubMed
3.
Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM: Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001, 20 (34): 4621-4628. 10.1038/sj.onc.1204621.CrossRefPubMed
4.
Birch JM, Heighway J, Teare MD, Kelsey AM, Hartley AL, Tricker KJ, Crowther D, Lane DP, Santibáñez-Koref MF: Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. Br J Cancer. 1994, 70 (6): 1176-1181. 10.1038/bjc.1994.468.CrossRefPubMedPubMedCentral
5.
Frebourg T, Barbier N, Yan YX, Garber JE, Dreyfus M, Fraumeni J, Li FP, Friend SH: Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet. 1995, 56 (3): 608-615.PubMedPubMedCentral
6.
Rapakko K, Allinen M, Syrjäkoski K, Vahteristo P, Huusko P, Vähäkangas K, Eerola H, Kainu T, Kallioniemi OP, Nevanlinna H, et al: Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. Br J Cancer. 2001, 84 (1): 116-119. 10.1054/bjoc.2000.1530.CrossRefPubMedPubMedCentral
7.
Lindor NM, McMaster ML, Lindor CJ, Greene MH, National Cancer Institute DoCP C.mmunity Oncology and Prevention Trials Research Group: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr. 2008, 38: 1-93.PubMed
8.
Huusko P, Castrén K, Launonen V, Soini Y, Pääkkönen K, Leisti J, Vähäkangas K, Winqvist R: Germ-line TP53 mutations in Finnish cancer families exhibiting features of the Li-Fraumeni syndrome and negative for BRCA1 and BRCA2. Cancer Genet Cytogenet. 1999, 112 (1): 9-14. 10.1016/S0165-4608(98)00258-1.CrossRefPubMed
9.
Lehman TA, Haffty BG, Carbone CJ, Bishop LR, Gumbs AA, Krishnan S, Shields PG, Modali R, Turner BC: Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res. 2000, 60 (4): 1062-1069.PubMed
10.
Lalloo F, Varley J, Ellis D, Moran A, O'Dair L, Pharoah P, Evans DG, Group EOBCS: Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet. 2003, 361 (9363): 1101-1102. 10.1016/S0140-6736(03)12856-5.CrossRefPubMed
11.
Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, et al: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006, 295 (12): 1379-1388. 10.1001/jama.295.12.1379.CrossRefPubMed
12.
13.
Chompret A: Clinical and molecular diagnosis of inherited breast-ovarian cancer. J Gynecol Obstet Biol Reprod (Paris). 2003, 32 (2): 101-119.
14.
15.
Børresen AL, Andersen TI, Garber J, Barbier-Piraux N, Thorlacius S, Eyfjörd J, Ottestad L, Smith-Sørensen B, Hovig E, Malkin D: Screening for germ line TP53 mutations in breast cancer patients. Cancer Res. 1992, 52 (11): 3234-3236.PubMed
16.
Evans DG, Wu CL, Birch JM: BRCA2: a cause of Li-Fraumeni-like syndrome. J Med Genet. 2008, 45 (1): 62-63.CrossRefPubMed
17.
Manoukian S, Peissel B, Pensotti V, Barile M, Cortesi L, Stacchiotti S, Terenziani M, Barbera F, Pasquini G, Frigerio S, et al: Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families. Eur J Cancer. 2007, 43 (3): 601-606. 10.1016/j.ejca.2006.09.024.CrossRefPubMed
18.
Lalloo F, Varley J, Moran A, Ellis D, O'dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S, et al: BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006, 42 (8): 1143-1150. 10.1016/j.ejca.2005.11.032.CrossRefPubMed
19.
Kuiper RP, Ligtenberg MJ, Hoogerbrugge N, Geurts van Kessel A: Germline copy number variation and cancer risk. Curr Opin Genet Dev. 2010, 20 (3): 282-289. 10.1016/j.gde.2010.03.005.CrossRefPubMed
20.
Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, D'Andrea E: Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet. 2003, 12 (9): 1055-1061. 10.1093/hmg/ddg120.CrossRefPubMed
21.
Woodward A, Davis T, Silva A, Kirk J, Leary J, Investigators K: Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet. 2005, 42 (5): e31-10.1136/jmg.2004.027961.CrossRefPubMedPubMedCentral
22.
Hansen TO, Jønson L, Albrechtsen A, Andersen MK, Ejlertsen B, Nielsen FC: Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat. 2009, 115 (2): 315-323. 10.1007/s10549-008-0088-0.CrossRefPubMed
23.
Hartmann C, John AL, Klaes R, Hofmann W, Bielen R, Koehler R, Janssen B, Bartram CR, Arnold N, Zschocke J: Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat. 2004, 24 (6): 534-CrossRefPubMed
24.
IARC - INTERNATIONAL AGENCY FOR RESEARCH ON CANCER: [http://​www.​iarc.​fr]
25.
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007, 28 (6): 622-629. 10.1002/humu.20495.CrossRefPubMed
26.
Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M, Mazoyer S, Coulet F, Hardouin A, Chompret A, et al: Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res. 2004, 64 (22): 8143-8147. 10.1158/0008-5472.CAN-04-2467.CrossRefPubMed
27.
Agata S, Dalla Palma M, Callegaro M, Scaini MC, Menin C, Ghiotto C, Nicoletto O, Zavagno G, Chieco-Bianchi L, D'Andrea E, et al: Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet. 2005, 42 (10): e64-10.1136/jmg.2005.032789.CrossRefPubMedPubMedCentral
28.
Pavlicek A, Noskov VN, Kouprina N, Barrett JC, Jurka J, Larionov V: Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. Hum Mol Genet. 2004, 13 (22): 2737-2751. 10.1093/hmg/ddh301.CrossRefPubMed
29.
Gad S, Klinger M, Caux-Moncoutier V, Pages-Berhouet S, Gauthier-Villars M, Coupier I, Bensimon A, Aurias A, Stoppa-Lyonnet D: Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families. J Med Genet. 2002, 39 (11): 817-821. 10.1136/jmg.39.11.817.CrossRefPubMedPubMedCentral
30.
Mazoyer S: Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat. 2005, 25 (5): 415-422. 10.1002/humu.20169.CrossRefPubMed
31.
Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy FeS, Kohlrausch F, Magno LA, Montenegro RC, Moraes MO, et al: The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011, 6 (2): e17063-10.1371/journal.pone.0017063.CrossRefPubMedPubMedCentral
32.
Li FP, Fraumeni JF: Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?. Ann Intern Med. 1969, 71 (4): 747-752.CrossRefPubMed
33.
Eeles RA: Germline mutations in the TP53 gene. Cancer Surv. 1995, 25: 101-124.PubMed
34.
Chompret A, Brugières L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, et al: P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000, 82 (12): 1932-1937.CrossRefPubMedPubMedCentral
35.
Chompret A, Abel A, Stoppa-Lyonnet D, Brugiéres L, Pagés S, Feunteun J, Bonaïti-Pellié C: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001, 38 (1): 43-47. 10.1136/jmg.38.1.43.CrossRefPubMedPubMedCentral
36.
Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, et al: The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett. 2007, 245 (1–2): 96-102.CrossRefPubMed
37.
NCCN - National Comprehensive Cancer Network: [http://​www.​nccn.​org]
38.
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002, 30 (12): e57-10.1093/nar/gnf056.CrossRefPubMedPubMedCentral
39.
Shlien A, Baskin B, Achatz MI, Stavropoulos DJ, Nichols KE, Hudgins L, Morel CF, Adam MP, Zhukova N, Rotin L, et al: A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes. Am J Hum Genet. 2010, 87 (5): 631-642. 10.1016/j.ajhg.2010.10.007.CrossRefPubMedPubMedCentral
40.
Krepischi A, Achatz M, Santos E, Costa S, Lisboa B, Brentani H, Santos T, Gonçalves A, Nóbrega A, Pearson P, et al: Germline DNA copy number variation in familial and early-onset breast cancer. Breast Cancer Res. 2012, in press
Metadata
Title
Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion
Authors
Amanda Gonçalves Silva
Ingrid Petroni Ewald
Marina Sapienza
Manuela Pinheiro
Ana Peixoto
Amanda França de Nóbrega
Dirce M Carraro
Manuel R Teixeira
Patricia Ashton-Prolla
Maria Isabel W Achatz
Carla Rosenberg
Ana C V Krepischi
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-237

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