Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Leora Witkowski, Jian Carrot-Zhang, Steffen Albrecht, Somayyeh Fahiminiya, Nancy Hamel, Eva Tomiak, David Grynspan, Emmanouil Saloustros, Javad Nadaf, Barbara Rivera, Catherine Gilpin, Ester Castellsagué, Rachel Silva-Smith, François Plourde, Mona Wu, Avi Saskin, Madeleine Arseneault, Rouzan G. Karabakhtsian, Elizabeth A. Reilly, Frederick R. UelandAnna Margiolaki, Kitty Pavlakis, Sharon M. Castellino, Janez Lamovec, Helen J. Mackay, Lawrence M. Roth, Thomas M. Ulbright, Tracey A. Bender, Vassilis Georgoulias, Michel Longy, Andrew Berchuck, Marc Tischkowitz, Inga Nagel, Reiner Siebert, Colin J R Stewart, Jocelyne Arseneau, W. Glenn McCluggage, Blaise A. Clarke, Yasser Riazalhosseini, Martin Hasselblatt, Jacek Majewski, William D. Foulkes

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190 Citations (Scopus)

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Original languageEnglish (US)
Pages (from-to)438-443
Number of pages6
JournalNature Genetics
Volume46
Issue number5
DOIs
StatePublished - 2014

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Small Cell Carcinoma
Ovary
Mutation
Germ-Line Mutation
Exome
Neoplasms
DNA
Genetic Counseling
Alleles
Cell Line
Proteins
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Witkowski, L., Carrot-Zhang, J., Albrecht, S., Fahiminiya, S., Hamel, N., Tomiak, E., ... Foulkes, W. D. (2014). Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nature Genetics, 46(5), 438-443. https://doi.org/10.1038/ng.2931

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. / Witkowski, Leora; Carrot-Zhang, Jian; Albrecht, Steffen; Fahiminiya, Somayyeh; Hamel, Nancy; Tomiak, Eva; Grynspan, David; Saloustros, Emmanouil; Nadaf, Javad; Rivera, Barbara; Gilpin, Catherine; Castellsagué, Ester; Silva-Smith, Rachel; Plourde, François; Wu, Mona; Saskin, Avi; Arseneault, Madeleine; Karabakhtsian, Rouzan G.; Reilly, Elizabeth A.; Ueland, Frederick R.; Margiolaki, Anna; Pavlakis, Kitty; Castellino, Sharon M.; Lamovec, Janez; Mackay, Helen J.; Roth, Lawrence M.; Ulbright, Thomas M.; Bender, Tracey A.; Georgoulias, Vassilis; Longy, Michel; Berchuck, Andrew; Tischkowitz, Marc; Nagel, Inga; Siebert, Reiner; Stewart, Colin J R; Arseneau, Jocelyne; McCluggage, W. Glenn; Clarke, Blaise A.; Riazalhosseini, Yasser; Hasselblatt, Martin; Majewski, Jacek; Foulkes, William D.

In: Nature Genetics, Vol. 46, No. 5, 2014, p. 438-443.

Research output: Contribution to journalArticle

Witkowski, L, Carrot-Zhang, J, Albrecht, S, Fahiminiya, S, Hamel, N, Tomiak, E, Grynspan, D, Saloustros, E, Nadaf, J, Rivera, B, Gilpin, C, Castellsagué, E, Silva-Smith, R, Plourde, F, Wu, M, Saskin, A, Arseneault, M, Karabakhtsian, RG, Reilly, EA, Ueland, FR, Margiolaki, A, Pavlakis, K, Castellino, SM, Lamovec, J, Mackay, HJ, Roth, LM, Ulbright, TM, Bender, TA, Georgoulias, V, Longy, M, Berchuck, A, Tischkowitz, M, Nagel, I, Siebert, R, Stewart, CJR, Arseneau, J, McCluggage, WG, Clarke, BA, Riazalhosseini, Y, Hasselblatt, M, Majewski, J & Foulkes, WD 2014, 'Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type', Nature Genetics, vol. 46, no. 5, pp. 438-443. https://doi.org/10.1038/ng.2931
Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nature Genetics. 2014;46(5):438-443. https://doi.org/10.1038/ng.2931
Witkowski, Leora ; Carrot-Zhang, Jian ; Albrecht, Steffen ; Fahiminiya, Somayyeh ; Hamel, Nancy ; Tomiak, Eva ; Grynspan, David ; Saloustros, Emmanouil ; Nadaf, Javad ; Rivera, Barbara ; Gilpin, Catherine ; Castellsagué, Ester ; Silva-Smith, Rachel ; Plourde, François ; Wu, Mona ; Saskin, Avi ; Arseneault, Madeleine ; Karabakhtsian, Rouzan G. ; Reilly, Elizabeth A. ; Ueland, Frederick R. ; Margiolaki, Anna ; Pavlakis, Kitty ; Castellino, Sharon M. ; Lamovec, Janez ; Mackay, Helen J. ; Roth, Lawrence M. ; Ulbright, Thomas M. ; Bender, Tracey A. ; Georgoulias, Vassilis ; Longy, Michel ; Berchuck, Andrew ; Tischkowitz, Marc ; Nagel, Inga ; Siebert, Reiner ; Stewart, Colin J R ; Arseneau, Jocelyne ; McCluggage, W. Glenn ; Clarke, Blaise A. ; Riazalhosseini, Yasser ; Hasselblatt, Martin ; Majewski, Jacek ; Foulkes, William D. / Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. In: Nature Genetics. 2014 ; Vol. 46, No. 5. pp. 438-443.
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abstract = "Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.",
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T1 - Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

AU - Witkowski, Leora

AU - Carrot-Zhang, Jian

AU - Albrecht, Steffen

AU - Fahiminiya, Somayyeh

AU - Hamel, Nancy

AU - Tomiak, Eva

AU - Grynspan, David

AU - Saloustros, Emmanouil

AU - Nadaf, Javad

AU - Rivera, Barbara

AU - Gilpin, Catherine

AU - Castellsagué, Ester

AU - Silva-Smith, Rachel

AU - Plourde, François

AU - Wu, Mona

AU - Saskin, Avi

AU - Arseneault, Madeleine

AU - Karabakhtsian, Rouzan G.

AU - Reilly, Elizabeth A.

AU - Ueland, Frederick R.

AU - Margiolaki, Anna

AU - Pavlakis, Kitty

AU - Castellino, Sharon M.

AU - Lamovec, Janez

AU - Mackay, Helen J.

AU - Roth, Lawrence M.

AU - Ulbright, Thomas M.

AU - Bender, Tracey A.

AU - Georgoulias, Vassilis

AU - Longy, Michel

AU - Berchuck, Andrew

AU - Tischkowitz, Marc

AU - Nagel, Inga

AU - Siebert, Reiner

AU - Stewart, Colin J R

AU - Arseneau, Jocelyne

AU - McCluggage, W. Glenn

AU - Clarke, Blaise A.

AU - Riazalhosseini, Yasser

AU - Hasselblatt, Martin

AU - Majewski, Jacek

AU - Foulkes, William D.

PY - 2014

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N2 - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

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