In the summer of 1999, a 12 year old girl, who was to become the first American patient with NUT midline carcinoma, developed a sore throat and difficulty swallowing, and eventually developed a muffled voice. There was no response to antibiotics, and a month later was seen by an otolaryngologist. Upon examination, an ulcerating mass was found to have replaced her epiglottis. The biopsy pathology resembled that of a nasopharyngeal carcinoma. She was treated accordingly, at Children’s Hospital, Boston, and enjoyed an initial shrinkage of her tumor, but the tumor came back and she died a horrible death, strangled by the tumor which closed off her airway. The clinicians would not forget this tumor, but the abrupt end to her life marked the discovery of a new type of cancer.
It was fortunate that the pathologists at Children’s Hospital had sent some of the patient’s initial biopsy to Dr. Paola Dal Cin of Brigham and Women’s Hospital for cytogenetic analysis. She found that this was no ordinary carcinoma, a class of solid tumors characterized by notoriously complex karyotypes. Apart from a trisomy 8, the patient’s tumor’s 47 xx karyotype harbored one distinct abnormality, a t(15;19)(q13;p13.1). The news of this karyotype was noticed by Dr. Jonathan Fletcher, who pays attention to rare, translocation-associated solid tumors. His review of the literature revealed the existence of three isolated case reports of pediatric thymic carcinomas with associated t(15;19)s, all aggressive and rapidly lethal, a clinical course which resembled that of the index patient [1
]. From one of these cases, which originated in Japan, Dr. Kubonishi had created a cell line [2
], Ty-82. With the purpose of cloning the presumed fusion oncogene resulting from the t(15;19) that was hypothetically responsible for creating this unusual and aggressive carcinoma, Dr. Fletcher acquired the cell line and handed over the gene mapping project to a very green yet eager post-doctoral fellow, this author.
Breakpoint mapping back then, 2000, had been made much easier with the newly available YAC and cosmid libraries that could be used to FISH-map rapidly. This was done for both the 15q13 and 19p13.1 loci in less than a year, and the loci were finely mapped by southern analysis. The chromosome 19 locus was located in the middle of a newly described gene, BRD4 [3
], and the chromosome 15 locus appeared to be very close to a small gene, Nop10p. Attempts to demonstrate that the Nop10p gene was present in a fusion transcript with BRD4 failed, however, and around that time a few new ESTs appeared within the area on the UCSC genome browser. Having failed to RACE out a product, we attempted RT-PCR using primers to these novel ESTs, and quickly succeeded at amplifying an in-frame fusion transcript between BRD4 and these ESTs. The ESTs collectively formed a putative 3.5kb gene that we initially called “PRUC”, for proline-rich in undifferentiated carcinoma. Unimpressed with this term, and having observed that it appeared to be expressed only in testis, as demonstrated in multiple tissue northern blotting [4
], we chose a more appropriate acronym, NUT, for Nuclear protein in testis. That name has since been changed to “chr15orf55” by the concensus of nomenclature rules, but we still use the name NUT. Hence, the name BRD4-NUT
for this fusion oncogene remains unchanged.
In the course of FISH-mapping the chromosome 19 and 15 breakpoints, we had developed some robust probes that could be used to screen new and archival tumors in search of more cases of what we termed, “t(15;19) carcinomas”. Our criteria were broad. We looked at all poorly differentiated carcinomas in patients younger than forty years of age, ignoring, for the time, adult carcinomas which were predicted to harbor 100s of mutations and complex karyotypes, a pathogenetic mechanism unlikely to overlap that of the t(15;19) carcinoma. We found seven tumors with NUT
rearrangements within 98 tumors screened [5
]. What was interesting was that while four of these were BRD4-NUT tumors, three had rearrangement of NUT
, but not BRD4
, termed NUT-variants
. This has led to the hypothesis that the common denominator was NUT
, and not BRD4
. Hence, after several iterations, the current name of this cancer is NUT midline carcinoma, or NMC, to reflect that it is a defined by chromosomal rearrangement of NUT