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

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

doi:10.1038/s41467-018-04950-x

R Tyler Hillman, Samantha Tippen + Show 13 more

Open Access

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.

Highlights

Adult-type granulosa cell tumors of the ovary are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation
We report the genomic analysis of 79 primary and recurrent Adult-type granulosa cell tumors of the ovary (aGCTs), a rare gynecologic malignancy which remains difficult to treat in the recurrent setting
The aGCT samples analyzed in these cohorts are genetically representative of this rare tumor type

Summary

Introduction

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. 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. We have used whole-exome and cancer gene panel sequencing to analyze 79 primary and recurrent aGCTs from two independent cohorts In both cohorts we identify truncating mutation of the histone lysine methyltransferase gene KMT2D ( known as MLL2) as a recurrent somatic event in aGCT. We found that mono-allelic KMT2D-truncating mutations are significantly more common in recurrent compared to primary aGCTs. immunohistochemistry (IHC) identified loss of KMT2D protein expression in some tumors without detectable KMT2D-truncating mutations, suggesting that non-genetic causes of KMT2D inactivation may occur in this tumor type. Our findings demonstrate an association between KMT2D inactivation and aGCT relapse, providing new insight into the molecular pathogenesis of this rare disease

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