A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer

Joseph Vijai, Sabine Topka, Danylo Villano, Vignesh Ravichandran, Kara N. Maxwell, Ann Maria, Tinu Thomas, Pragna Gaddam, Anne Lincoln, Sarah Kazzaz, Brandon Wenz, Shai Carmi, Kasmintan A. Schrader, Steven Hart, Steve M. Lipkin, Susan L. Neuhausen, Michael F. Walsh, Liying Zhang, Flavio Lejbkowicz, Hedy RennertZsofia K. Stadler, Mark Robson, Jeffrey N. Weitzel, Susan Domchek, Mark J. Daly, Fergus J Couch, Katherine L. Nathanson, Larry Norton, Gad Rennert, Kenneth Offit

Research output: Contribution to journalArticle

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Abstract

Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR BC = 1.53, OR ER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers.

Original languageEnglish (US)
Pages (from-to)1267-1275
Number of pages9
JournalCancer Discovery
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2016

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Breast Neoplasms
Mutation
Clustered Regularly Interspaced Short Palindromic Repeats
DNA Repair-Deficiency Disorders
Exome
Cell Line
Chromosomes, Human, Pair 6
Penetrance
Alkylating Agents
DNA
Mutation Rate
Mutant Proteins
DNA Repair
Estrogen Receptors
Genes
Adenosine Triphosphate
Phenotype
Neoplasms
Proteins
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Vijai, J., Topka, S., Villano, D., Ravichandran, V., Maxwell, K. N., Maria, A., ... Offit, K. (2016). A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer. Cancer Discovery, 6(11), 1267-1275. https://doi.org/10.1158/2159-8290.CD-16-0487

A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer. / Vijai, Joseph; Topka, Sabine; Villano, Danylo; Ravichandran, Vignesh; Maxwell, Kara N.; Maria, Ann; Thomas, Tinu; Gaddam, Pragna; Lincoln, Anne; Kazzaz, Sarah; Wenz, Brandon; Carmi, Shai; Schrader, Kasmintan A.; Hart, Steven; Lipkin, Steve M.; Neuhausen, Susan L.; Walsh, Michael F.; Zhang, Liying; Lejbkowicz, Flavio; Rennert, Hedy; Stadler, Zsofia K.; Robson, Mark; Weitzel, Jeffrey N.; Domchek, Susan; Daly, Mark J.; Couch, Fergus J; Nathanson, Katherine L.; Norton, Larry; Rennert, Gad; Offit, Kenneth.

In: Cancer Discovery, Vol. 6, No. 11, 01.11.2016, p. 1267-1275.

Research output: Contribution to journalArticle

Vijai, J, Topka, S, Villano, D, Ravichandran, V, Maxwell, KN, Maria, A, Thomas, T, Gaddam, P, Lincoln, A, Kazzaz, S, Wenz, B, Carmi, S, Schrader, KA, Hart, S, Lipkin, SM, Neuhausen, SL, Walsh, MF, Zhang, L, Lejbkowicz, F, Rennert, H, Stadler, ZK, Robson, M, Weitzel, JN, Domchek, S, Daly, MJ, Couch, FJ, Nathanson, KL, Norton, L, Rennert, G & Offit, K 2016, 'A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer', Cancer Discovery, vol. 6, no. 11, pp. 1267-1275. https://doi.org/10.1158/2159-8290.CD-16-0487
Vijai J, Topka S, Villano D, Ravichandran V, Maxwell KN, Maria A et al. A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer. Cancer Discovery. 2016 Nov 1;6(11):1267-1275. https://doi.org/10.1158/2159-8290.CD-16-0487
Vijai, Joseph ; Topka, Sabine ; Villano, Danylo ; Ravichandran, Vignesh ; Maxwell, Kara N. ; Maria, Ann ; Thomas, Tinu ; Gaddam, Pragna ; Lincoln, Anne ; Kazzaz, Sarah ; Wenz, Brandon ; Carmi, Shai ; Schrader, Kasmintan A. ; Hart, Steven ; Lipkin, Steve M. ; Neuhausen, Susan L. ; Walsh, Michael F. ; Zhang, Liying ; Lejbkowicz, Flavio ; Rennert, Hedy ; Stadler, Zsofia K. ; Robson, Mark ; Weitzel, Jeffrey N. ; Domchek, Susan ; Daly, Mark J. ; Couch, Fergus J ; Nathanson, Katherine L. ; Norton, Larry ; Rennert, Gad ; Offit, Kenneth. / A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer. In: Cancer Discovery. 2016 ; Vol. 6, No. 11. pp. 1267-1275.
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abstract = "Known gene mutations account for approximately 50{\%} of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR BC = 1.53, OR ER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers.",
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T1 - A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer

AU - Vijai, Joseph

AU - Topka, Sabine

AU - Villano, Danylo

AU - Ravichandran, Vignesh

AU - Maxwell, Kara N.

AU - Maria, Ann

AU - Thomas, Tinu

AU - Gaddam, Pragna

AU - Lincoln, Anne

AU - Kazzaz, Sarah

AU - Wenz, Brandon

AU - Carmi, Shai

AU - Schrader, Kasmintan A.

AU - Hart, Steven

AU - Lipkin, Steve M.

AU - Neuhausen, Susan L.

AU - Walsh, Michael F.

AU - Zhang, Liying

AU - Lejbkowicz, Flavio

AU - Rennert, Hedy

AU - Stadler, Zsofia K.

AU - Robson, Mark

AU - Weitzel, Jeffrey N.

AU - Domchek, Susan

AU - Daly, Mark J.

AU - Couch, Fergus J

AU - Nathanson, Katherine L.

AU - Norton, Larry

AU - Rennert, Gad

AU - Offit, Kenneth

PY - 2016/11/1

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N2 - Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR BC = 1.53, OR ER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers.

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