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A dominantly inherited 5'UTR variant causing methylation associated silencing of BRCA1 as a cause of breast and ovarian cancer

A dominantly inherited 5'UTR variant causing methylation associated silencing of BRCA1 as a cause of breast and ovarian cancer
A dominantly inherited 5'UTR variant causing methylation associated silencing of BRCA1 as a cause of breast and ovarian cancer
Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.−107A>T in the BRCA1 5′ UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5′ UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.
doi.org/10.1016/j.ajhg.2018.07.002
0002-9297
213-220
Evans, D.Gareth R.
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van Veen, Elke M.
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Byers, Helen J.
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Wallace, Andrew J.
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Ellingford, Jamie M.
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Beaman, Glenda
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Santoyo-Lopez, Javier
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Aitman, Timothy J.
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Eccles, Diana
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Lalloo, Fiona I.
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Smith, Miriam J.
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Newman, William G.
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Evans, D.Gareth R.
ee001bc1-9b29-4a58-a251-a27b18eff669
van Veen, Elke M.
24692869-c7e5-44f9-b99d-682f38c13fc6
Byers, Helen J.
bd8b9d81-a692-4534-8bce-b152553d6995
Wallace, Andrew J.
31501286-9c2e-4c8e-9985-cc2244c26249
Ellingford, Jamie M.
e84f25d6-9c76-44e8-b764-1ec81825032e
Beaman, Glenda
859d91d0-c4e6-4836-80ed-0b8ca4e8da4d
Santoyo-Lopez, Javier
ec235066-f5a9-4ca1-bd3a-01f64211eae2
Aitman, Timothy J.
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Eccles, Diana
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Lalloo, Fiona I.
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Smith, Miriam J.
ec330621-45fe-4e90-aa9a-062084c36a48
Newman, William G.
771e4904-12d6-4b02-8f3f-a0285d95f1a7

Evans, D.Gareth R., van Veen, Elke M., Byers, Helen J., Wallace, Andrew J., Ellingford, Jamie M., Beaman, Glenda, Santoyo-Lopez, Javier, Aitman, Timothy J., Eccles, Diana, Lalloo, Fiona I., Smith, Miriam J. and Newman, William G. (2018) A dominantly inherited 5'UTR variant causing methylation associated silencing of BRCA1 as a cause of breast and ovarian cancer. The American Journal of Human Genetics, 103 (2), 213-220. (doi.org/10.1016/j.ajhg.2018.07.002).

Record type: Article

Abstract

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.−107A>T in the BRCA1 5′ UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5′ UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.

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Accepted/In Press date: 29 June 2018
e-pub ahead of print date: 2 August 2018
Published date: 2 August 2018

Identifiers

Local EPrints ID: 422093
URI: https://eprints.soton.ac.uk/id/eprint/422093
DOI: doi.org/10.1016/j.ajhg.2018.07.002
ISSN: 0002-9297
PURE UUID: df6c8b38-6794-4edb-90a4-d8a7037a8cfc

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Date deposited: 16 Jul 2018 16:30
Last modified: 19 Jul 2019 17:09

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Contributors

Author: D.Gareth R. Evans
Author: Elke M. van Veen
Author: Helen J. Byers
Author: Andrew J. Wallace
Author: Jamie M. Ellingford
Author: Glenda Beaman
Author: Javier Santoyo-Lopez
Author: Timothy J. Aitman
Author: Diana Eccles
Author: Fiona I. Lalloo
Author: Miriam J. Smith
Author: William G. Newman

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