Aims: Tumors of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumor (MMGC/T) components are usually diagnosed in postmenopausal women and pursue an aggressive clinical course characterized by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of 9 MMGC/T, including 7 tumors containing yolk sac tumor (YST), 1 tumor containing choriocarcinoma and 1 tumor containing epithelioid trophoblastic tumor. The objectives were: 1) to investigate whether MMGC/T show a distinct genetic profile and 2) to explore the relationship between the different histologic components.

Methods and results: Next generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumor were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in post-pubertal germ cell tumors and gestational trophoblastic tumors were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (8/9) were characterized by a complex copy number variant profile including numerous focal, regional, arm-level and chromosome-level events.

Conclusions: Comparison of paired samples supports that the YST and trophoblastic tumor components of MMGC/T have a somatic and often show numerous copy number variants suggestive of underlying genomic instability.