Molecular analysis of NUT‐positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions

Abstract

Background Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1‐MAML2, YAP1‐NUTM1, and infrequently WWTR1‐NUTM1; YAP1‐NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1‐translocated tumors. This study sought to investigate potential novel NUTM1‐fusion partners among NUT IHC‐positive poromas and porocarcinomas. Methods Thirteen NUT IHC‐positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi‐institutional international cohort. Next‐generation sequencing (NGS) assessed for NUTM1 fusion partners. Results NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1‐NUTM1 (11/12 cases) and WWTR1‐NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read‐spanning YAP1‐NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. Conclusion While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1‐NUTM1 fusion was detected in 11 cases (92%) and WWTR1‐NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

YAP1::MAML2 fusions in poromatosis: A report of two patients

“…17 Poromas with NUTM1 fusions exhibited diffuse nuclear positivity for NUT. 11,[18][19][20] In the present cases, none of the lesions exhibited NUT expression. All poromas harbored YAP1::MAML2 fusions in the present two cases and the previously reported case 12 of poromatosis, but not YAP1::NUTM1.…”

“…The loss of positivity for YAP1‐C appears to be a surrogate marker for YAP1 fusion in poromas 16 and other neoplasms 17 . Poromas with NUTM1 fusions exhibited diffuse nuclear positivity for NUT 11,18–20 . In the present cases, none of the lesions exhibited NUT expression.…”

Diagnosis and Management of Porocarcinoma

“…For this reason, the proteins produced by fused genes can lead to oncogenesis. [ 34 , 35 ] Recently, the relationship between gene fusion and PC oncogenesis has become clearer. Sekine et al reported that highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions were found in 92 of 104 poroma cases (88.5%) and in 7 of 11 PC cases (63.6%) [ 36 ].…”

“…The tumor specimens in all cases of poromas (two cases) and PC (three cases) with YAP-NUTM1 fusion showed positive immunostaining for NUT. Snow et al assessed NUTM1 gene fusions using 13 immunohistochemically NUT-positive poroid tumors [ 35 ]. NUTM1 fusion was detected in 12 of 13 cases through deep sequencing, and YAP1–NUTM1 fusion was identified in 11 of 12 cases.…”

Cuticular Poroma: A Rare Poroma Variant Simulating a Malignant Neoplasm That Often Harbors YAP1::NUTM1 Fusions Similar to Their Conventional Counterparts

“…Of the 13 cases studied by Snow et all, 11 lesions yielded YAP1::NUTM1 fusion, and in 1 case, WWTR1::NUTM1 fusion was found. 7 All the tumors were immunopositive for NUT. Other authors also demonstrated the utility of immunohistochemistry and molecular biology in the diagnosis of poroid tumors.…”