Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability 

Abstract

Aims Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised 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 nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components. Methods and results Next‐generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non‐Mullerian components of the tumour 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 postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair‐proficient MMGC/T (eight of nine) were characterised 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 tumour components of MMGC/T have a somatic origin and often show numerous copy‐number variants, suggestive of underlying genomic instability.

Ovarian clear cell carcinoma with an immature teratoma component showing ARID1A deficiency and an identical PIK3CA mutation

“…Recent studies genetically analyzed ovarian and uterine tumors with a combination of epithelial tumor components and YST or trophoblastic tumor components using targeted next-generation sequencing. [7][8][9] The findings obtained revealed that both components shared identical mutations that generally involved epithelial tumor development, such as PTEN, PIK3CA, KRAS, BRAF, CTNNB1, ARID1A, and TP53. [7][8][9] A mutation analysis of immature teratoma associated with an epithelial tumor had not been conducted until the present case.…”

“…[7][8][9] The findings obtained revealed that both components shared identical mutations that generally involved epithelial tumor development, such as PTEN, PIK3CA, KRAS, BRAF, CTNNB1, ARID1A, and TP53. [7][8][9] A mutation analysis of immature teratoma associated with an epithelial tumor had not been conducted until the present case. Clear cell carcinoma and immature teratoma in the present case both showed the loss of ARID1A and an identical PIK3CA mutation, which are common abnormalities of ovarian clear cell carcinoma that frequently coexist.…”

“…In addition, isochromosome 12p, which is frequently found in YST of a germ cell origin, was absent in YST components in a previous study. 8 Therefore, germ cell tumor components may be somatically derived from existing epithelial tumors.…”

“…In a previous study, ovarian and uterine tumors with epithelial and germ cell or trophoblastic components harbored a complex copy-number variant profile, which showed different copy-number gains and losses in many chromosomes between the two components. 8 Genomic instability was proposed as the origin of these tumors. 8 Another potential mechanism is epigenetic changes, which may result in a different transcriptional status and protein expression in a germ cell tumor component.…”

Extrauterine Mesonephric-like Neoplasms

“…These neoplasms usually occur in postmenopausal patients and exhibit an aggressive clinical behavior. [26][27][28][29][30][31][32][33][34] Several recent molecular studies have helped confirm a somatic origin of the germ cell component in these neoplasms given the similar mutational profiles in both tumor components, which have generally been those expected in the Mullerian component. Other features in favor of a somatic origin for the germ cell component include lack of i( 12)p (see below), their frequent presentation in postmenopausal women (an age group where germ cell tumors, especially YST, are uncommon) and their suboptimal response to germ cellrelated chemotherapy.…”