Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas

Kathryn P. Pennington, Tom Walsh, Maria I. Harrell, Ming K. Lee, Christopher C. Pennil, Mara H. Rendi, Anne Thornton, Barbara M. Norquist, Silvia Casadei, Alexander Nord, Kathy J. Agnew, Colin C. Pritchard, Sheena Scroggins, Rochelle L. Garcia, Mary Claire King, Elizabeth M. Swisher

Research output: Contribution to journalArticle

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Abstract

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Original languageEnglish (US)
Pages (from-to)764-775
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number3
DOIs
StatePublished - Feb 11 2014
Externally publishedYes

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Fallopian Tubes
Germ-Line Mutation
Homologous Recombination
Platinum
Carcinoma
Mutation
Genes
BRCA1 Gene
BRCA2 Gene
Carcinosarcoma
Recombinational DNA Repair
High-Throughput Nucleotide Sequencing
Histology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. / Pennington, Kathryn P.; Walsh, Tom; Harrell, Maria I.; Lee, Ming K.; Pennil, Christopher C.; Rendi, Mara H.; Thornton, Anne; Norquist, Barbara M.; Casadei, Silvia; Nord, Alexander; Agnew, Kathy J.; Pritchard, Colin C.; Scroggins, Sheena; Garcia, Rochelle L.; King, Mary Claire; Swisher, Elizabeth M.

In: Clinical Cancer Research, Vol. 20, No. 3, 11.02.2014, p. 764-775.

Research output: Contribution to journalArticle

Pennington, KP, Walsh, T, Harrell, MI, Lee, MK, Pennil, CC, Rendi, MH, Thornton, A, Norquist, BM, Casadei, S, Nord, A, Agnew, KJ, Pritchard, CC, Scroggins, S, Garcia, RL, King, MC & Swisher, EM 2014, 'Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas', Clinical Cancer Research, vol. 20, no. 3, pp. 764-775. https://doi.org/10.1158/1078-0432.CCR-13-2287
Pennington, Kathryn P. ; Walsh, Tom ; Harrell, Maria I. ; Lee, Ming K. ; Pennil, Christopher C. ; Rendi, Mara H. ; Thornton, Anne ; Norquist, Barbara M. ; Casadei, Silvia ; Nord, Alexander ; Agnew, Kathy J. ; Pritchard, Colin C. ; Scroggins, Sheena ; Garcia, Rochelle L. ; King, Mary Claire ; Swisher, Elizabeth M. / Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 3. pp. 764-775.
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abstract = "Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24{\%}) and/or somatic (9{\%}) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28{\%} vs. 31{\%}, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.",
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T1 - Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas

AU - Pennington, Kathryn P.

AU - Walsh, Tom

AU - Harrell, Maria I.

AU - Lee, Ming K.

AU - Pennil, Christopher C.

AU - Rendi, Mara H.

AU - Thornton, Anne

AU - Norquist, Barbara M.

AU - Casadei, Silvia

AU - Nord, Alexander

AU - Agnew, Kathy J.

AU - Pritchard, Colin C.

AU - Scroggins, Sheena

AU - Garcia, Rochelle L.

AU - King, Mary Claire

AU - Swisher, Elizabeth M.

PY - 2014/2/11

Y1 - 2014/2/11

N2 - Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

AB - Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

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