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Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation

Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation
Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation
Background Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. Methods Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). Results No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher’s exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4–83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3–83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. Discussion These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.
0022-2593
209-219
Frayling, Ian M
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Mautner, Victor-felix
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Baralle, Diana
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Cox, Harriet
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Eccles, Diana M
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Rogers, Mark T
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Frayling, Ian M
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Baralle, Diana
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Frayling, Ian M, Mautner, Victor-felix, Van Minkelen, Rick, Kallionpaa, Roope A, Aktaş, Safiye, Baralle, Diana, Ben-shachar, Shay, Callaway, Alison, Cox, Harriet, Eccles, Diana M, Ferkal, Salah, Laduca, Holly, Lázaro, Conxi, Rogers, Mark T, Stuenkel, Aaron J, Summerour, Pia, Varan, Ali, Yap, Yoon Sim, Zehou, Ouidad, Peltonen, Juha, Gareth, Evans D., Wolkenstein, Pierre and Upadhyaya, Meena (2019) Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. Journal of Medical Genetics, 56 (4), 209-219. (doi:10.1136/jmedgenet-2018-105599).

Record type: Article

Abstract

Background Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. Methods Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). Results No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher’s exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4–83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3–83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. Discussion These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.

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jmedgenet-2018-105599 revised - Accepted Manuscript
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Accepted/In Press date: 15 November 2018
e-pub ahead of print date: 10 December 2018
Published date: 1 April 2019

Identifiers

Local EPrints ID: 426868
URI: http://eprints.soton.ac.uk/id/eprint/426868
ISSN: 0022-2593
PURE UUID: f2c8ad18-54b5-4753-95b8-452e02a532e3
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Diana M Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 14 Dec 2018 17:30
Last modified: 26 Nov 2021 02:53

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Contributors

Author: Ian M Frayling
Author: Victor-felix Mautner
Author: Rick Van Minkelen
Author: Roope A Kallionpaa
Author: Safiye Aktaş
Author: Diana Baralle ORCID iD
Author: Shay Ben-shachar
Author: Alison Callaway
Author: Harriet Cox
Author: Diana M Eccles ORCID iD
Author: Salah Ferkal
Author: Holly Laduca
Author: Conxi Lázaro
Author: Mark T Rogers
Author: Aaron J Stuenkel
Author: Pia Summerour
Author: Ali Varan
Author: Yoon Sim Yap
Author: Ouidad Zehou
Author: Juha Peltonen
Author: Evans D. Gareth
Author: Pierre Wolkenstein
Author: Meena Upadhyaya

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