KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary

R. Tyler Hillman; Joseph Celestino; Christopher Terranova; Hannah C. Beird; Curtis Gumbs; Latasha Little; Tri Nguyen; Rebecca Thornton; Samantha Tippen; Jianhua Zhang; Karen H. Lu; David M. Gershenson; Kunal Rai; Russell R. Broaddus; P. Andrew Futreal

doi:10.1038/s41467-018-04950-x

KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary

R. Tyler Hillman, Joseph Celestino, Christopher Terranova, Hannah C. Beird, Curtis Gumbs, Latasha Little, Tri Nguyen, Rebecca Thornton, Samantha Tippen, Jianhua Zhang, Karen H. Lu, David M. Gershenson, Kunal Rai, Russell R. Broaddus, P. Andrew Futreal

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Abstract

Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.

Original language	English (US)
Article number	2496
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04950-x
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Hillman, R. T., Celestino, J., Terranova, C., Beird, H. C., Gumbs, C., Little, L., Nguyen, T., Thornton, R., Tippen, S., Zhang, J., Lu, K. H., Gershenson, D. M., Rai, K., Broaddus, R. R., & Futreal, P. A. (2018). KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary. Nature communications, 9(1), Article 2496. https://doi.org/10.1038/s41467-018-04950-x

Hillman, RT, Celestino, J, Terranova, C , Beird, HC, Gumbs, C, Little, L, Nguyen, T, Thornton, R, Tippen, S, Zhang, J, Lu, KH, Gershenson, DM, Rai, K, Broaddus, RR & Futreal, PA 2018, 'KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary', Nature communications, vol. 9, no. 1, 2496. https://doi.org/10.1038/s41467-018-04950-x

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abstract = "Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.",

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AU - Gumbs, Curtis

AU - Little, Latasha

AU - Nguyen, Tri

AU - Thornton, Rebecca

AU - Tippen, Samantha

AU - Zhang, Jianhua

AU - Lu, Karen H.

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AU - Broaddus, Russell R.

AU - Futreal, P. Andrew

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N2 - Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.

AB - Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.

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KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary

Abstract

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