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 and P. Andrew Futreal ()
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R. Tyler Hillman: The University of Texas MD Anderson Cancer Center
Joseph Celestino: The University of Texas MD Anderson Cancer Center
Christopher Terranova: The University of Texas MD Anderson Cancer Center
Hannah C. Beird: The University of Texas MD Anderson Cancer Center
Curtis Gumbs: The University of Texas MD Anderson Cancer Center
Latasha Little: The University of Texas MD Anderson Cancer Center
Tri Nguyen: The University of Texas MD Anderson Cancer Center
Rebecca Thornton: The University of Texas MD Anderson Cancer Center
Samantha Tippen: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Karen H. Lu: The University of Texas MD Anderson Cancer Center
David M. Gershenson: The University of Texas MD Anderson Cancer Center
Kunal Rai: The University of Texas MD Anderson Cancer Center
Russell R. Broaddus: The University of Texas MD Anderson Cancer Center
P. Andrew Futreal: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04950-x

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