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

• Published in: Nature communications Vol. 9; no. 1; pp. 2496 - 7
• Main Authors: Hillman, R. Tyler, Celestino, Joseph, Terranova, Christopher, Beird, Hannah C., Gumbs, Curtis, Little, Latasha, Nguyen, Tri, Thornton, Rebecca, Tippen, Samantha, Zhang, Jianhua, Lu, Karen H., Gershenson, David M., Rai, Kunal, Broaddus, Russell R., Futreal, P. Andrew
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.06.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 45/22; 45/23; 631/208/212/2301; 631/67/1517/1709; Adult; Aged; Alleles; Cancer; Cell Nucleus - metabolism; Deactivation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene sequencing; Granulosa Cell Tumor - genetics; Granulosa Cell Tumor - pathology; Health risks; Humanities and Social Sciences; Humans; Inactivation; Lysine; Methyltransferase; Middle Aged; multidisciplinary; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Ovary - cytology; Ovary - pathology; Retrospective Studies; Risk assessment; Science; Science (multidisciplinary); Tumors; Whole Exome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04950-x

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. Adult-type granulosa cell tumors of the ovary (aGCTs) are rare and recurrence is difficult to treat. Here, the authors observe in aGCT a novel recurrent somatic truncating mutation of KMT2D, more frequent in recurrent aGCT, and also non-genetic loss of KMT2D expression.