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 N. Hart; Steve M. Lipkin; Susan L. Neuhausen; Michael F. Walsh; Liying Zhang; Flavio Lejbkowicz; Hedy Rennert; Zsofia K. Stadler; Mark Robson; Jeffrey N. Weitzel; Susan Domchek; Mark J. Daly; Fergus J. Couch; Katherine L. Nathanson; Larry Norton; Gad Rennert; Kenneth Offit

doi:10.1158/2159-8290.CD-16-0487

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 N. 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^*

^*Corresponding author for this work

Department of Social Medicine

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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 language	American English
Pages (from-to)	1267-1275
Number of pages	9
Journal	Cancer Discovery
Volume	6
Issue number	11
DOIs	https://doi.org/10.1158/2159-8290.CD-16-0487
State	Published - Nov 2016

Bibliographical note

Funding Information:
This work was supported by the Sharon Corzine Cancer Research Fund, The Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Miele family initiative (K. Offit), and the Andrew Sabin Family Fund. This work was also supported by NIH R01CA176785 and the Breast Cancer Research Foundation (F.J. Couch, K.L. Nathanson, M. Robson, and K. Offit), R21-CA139396 (J. Vijai and Z.K. Stadler), and Department of Defense W81XWH-13-1-0338 (K.L. Nathanson). This work was also supported by funds from the City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. This work was also supported by the MSKCC Core grant NIH P30CA008748.

Publisher Copyright:
© 2016 American Association for Cancer Research.

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Vijai, J., Topka, S., Villano, D., Ravichandran, V., Maxwell, K. N., Maria, A., Thomas, T., Gaddam, P., Lincoln, A., Kazzaz, S., Wenz, B., Carmi, S., Schrader, K. A., Hart, S. N., Lipkin, S. M., Neuhausen, S. L., Walsh, M. F., Zhang, L., Lejbkowicz, F., ... 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

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title = "A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer",

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.",

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

note = "Funding Information: This work was supported by the Sharon Corzine Cancer Research Fund, The Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Miele family initiative (K. Offit), and the Andrew Sabin Family Fund. This work was also supported by NIH R01CA176785 and the Breast Cancer Research Foundation (F.J. Couch, K.L. Nathanson, M. Robson, and K. Offit), R21-CA139396 (J. Vijai and Z.K. Stadler), and Department of Defense W81XWH-13-1-0338 (K.L. Nathanson). This work was also supported by funds from the City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. This work was also supported by the MSKCC Core grant NIH P30CA008748. Publisher Copyright: {\textcopyright} 2016 American Association for Cancer Research.",

year = "2016",

month = nov,

doi = "10.1158/2159-8290.CD-16-0487",

language = "American English",

volume = "6",

pages = "1267--1275",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "11",

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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, SN, 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

TY - JOUR

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 N.

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

N1 - Funding Information: This work was supported by the Sharon Corzine Cancer Research Fund, The Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Miele family initiative (K. Offit), and the Andrew Sabin Family Fund. This work was also supported by NIH R01CA176785 and the Breast Cancer Research Foundation (F.J. Couch, K.L. Nathanson, M. Robson, and K. Offit), R21-CA139396 (J. Vijai and Z.K. Stadler), and Department of Defense W81XWH-13-1-0338 (K.L. Nathanson). This work was also supported by funds from the City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. This work was also supported by the MSKCC Core grant NIH P30CA008748. Publisher Copyright: © 2016 American Association for Cancer Research.

PY - 2016/11

Y1 - 2016/11

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.

AB - 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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U2 - 10.1158/2159-8290.CD-16-0487

DO - 10.1158/2159-8290.CD-16-0487

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JO - Cancer Discovery

JF - Cancer Discovery

IS - 11

ER -

A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer

Abstract

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