BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

Kathryn P. Pennington, Tom Walsh, Ming Lee, Christopher Pennil, Akiva P. Novetsky, Kathy J. Agnew, Anne Thornton, Rochelle Garcia, David Mutch, Mary Claire King, Paul Goodfellow, Elizabeth M. Swisher

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Background: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. Results: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. Conclusions: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

Original languageEnglish (US)
Pages (from-to)332-338
Number of pages7
JournalCancer
Volume119
Issue number2
DOIs
StatePublished - Jan 15 2013
Externally publishedYes

Fingerprint

Checkpoint Kinase 2
BRCA1 Protein
Germ-Line Mutation
Carcinoma
Mutation
Breast Neoplasms
Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Mutation Rate
Tumor Suppressor Genes
Histology
Proteins
Li-Fraumeni Syndrome
Hereditary Neoplastic Syndromes
Genes
Fanconi Anemia
High-Throughput Nucleotide Sequencing
Genetic Testing
History

Keywords

  • BRCA1 gene
  • BRCA2 gene
  • Lynch syndrome
  • molecular genetics
  • uterine serous carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pennington, K. P., Walsh, T., Lee, M., Pennil, C., Novetsky, A. P., Agnew, K. J., ... Swisher, E. M. (2013). BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer, 119(2), 332-338. https://doi.org/10.1002/cncr.27720

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. / Pennington, Kathryn P.; Walsh, Tom; Lee, Ming; Pennil, Christopher; Novetsky, Akiva P.; Agnew, Kathy J.; Thornton, Anne; Garcia, Rochelle; Mutch, David; King, Mary Claire; Goodfellow, Paul; Swisher, Elizabeth M.

In: Cancer, Vol. 119, No. 2, 15.01.2013, p. 332-338.

Research output: Contribution to journalArticle

Pennington, KP, Walsh, T, Lee, M, Pennil, C, Novetsky, AP, Agnew, KJ, Thornton, A, Garcia, R, Mutch, D, King, MC, Goodfellow, P & Swisher, EM 2013, 'BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma', Cancer, vol. 119, no. 2, pp. 332-338. https://doi.org/10.1002/cncr.27720
Pennington KP, Walsh T, Lee M, Pennil C, Novetsky AP, Agnew KJ et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013 Jan 15;119(2):332-338. https://doi.org/10.1002/cncr.27720
Pennington, Kathryn P. ; Walsh, Tom ; Lee, Ming ; Pennil, Christopher ; Novetsky, Akiva P. ; Agnew, Kathy J. ; Thornton, Anne ; Garcia, Rochelle ; Mutch, David ; King, Mary Claire ; Goodfellow, Paul ; Swisher, Elizabeth M. / BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. In: Cancer. 2013 ; Vol. 119, No. 2. pp. 332-338.
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abstract = "Background: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10{\%} serous histology were also assessed. Results: Seven subjects (4.6{\%}) carried germline loss-of-function mutations: 3 subjects (2.0{\%}) with mutations in BRCA1, 2 subjects (1.3{\%}) with mutations in TP53, and 2 subjects (1.3{\%}) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10{\%} serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9{\%}, compared to 0.9{\%} in 119 women with no such history. Conclusions: Approximately 5{\%} of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2{\%} is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.",
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AU - Pennington, Kathryn P.

AU - Walsh, Tom

AU - Lee, Ming

AU - Pennil, Christopher

AU - Novetsky, Akiva P.

AU - Agnew, Kathy J.

AU - Thornton, Anne

AU - Garcia, Rochelle

AU - Mutch, David

AU - King, Mary Claire

AU - Goodfellow, Paul

AU - Swisher, Elizabeth M.

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N2 - Background: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. Results: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. Conclusions: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

AB - Background: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. Results: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. Conclusions: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

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KW - BRCA2 gene

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