Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Abstract

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

Emerging entities in NUTM1‐rearranged neoplasms

“…Over the last several years evidence has accumulated that NUTM1 rearrangements can be found outside the standard clinicopathologic setting of NC. Of particular interest, several members of the MAX Dimerization ( MAD ) gene family, including MXD1 , MXD4 , and MGA have now been identified as NUTM1 fusion partners. Tumors with MAD‐NUTM1 fusions have overlapping histopathological features with NCs, but overall are less differentiated as determined by both morphology and IHC.…”

“…Tumors with MAD‐NUTM1 fusions have overlapping histopathological features with NCs, but overall are less differentiated as determined by both morphology and IHC. They are typically composed of sheets of round or mixed round/spindled cells, sometimes with rhabdoid or giant cells . Importantly, morphological evidence of epithelial differentiation, including the abrupt keratinizing foci seen in NCs, is absent in MAD‐NUTM1 tumors.…”

“…A few are associated with distinctive matrix including collagenous “amianthoid” fibres or chondroid differentiation . The undifferentiated morphology is borne out by IHC, which typically shows variable expression of the nonspecific markers CD99, CD34, and BCL2, and no expression of cytokeratins, p63/p40, EMA, S100, GFAP, neuroendocrine markers, or lymphoid markers . Since only very few MAD‐NUTM1 tumors have been identified, variations on this expression prolife may be encountered in the future.…”

“…Although the information is currently limited, it appears that, like NCs, additional somatic cancer driver mutations are rare in these tumors. Two cases of whole genome sequencing and one of whole exome sequencing have both failed to find additional significant cancer driver mutations or evidence of chromoplexy. Although the total cases are again limited, the clinical course of MAD‐NUTM1 tumors seems more positive that NCs.…”

Primary malignant epithelioid and rhabdoid tumor of bone harboring ZNF532‐NUTM1 fusion: the expanding NUT cancer family

“…2 With high sensitivity (87%) and specificity (100%), NUT immunostain has been utilized as a diagnostic substitute for molecular testing. [5][6][7][8][9][10][11][12][13] These tumors exhibit a wider and more heterogeneous morphologic spectrum compared to typical NC. 4 Recently, NUTM1 gene rearrangements have been increasingly identified in other cancers.…”