NUT Carcinoma—An Underdiagnosed Malignancy

Abstract

NUT carcinoma (NC) is a rare and highly aggressive malignancy with a dismal prognosis and a median survival of 6–9 months only. Although very few cases of NC are reported each year, the true prevalence is estimated to be much higher, with NC potentially widely underdiagnosed due to the lack of awareness. NC primarily occurs in midline structures including thorax, head, and neck; however, other sites such as pancreas and kidney are also affected, albeit at lower frequencies. NC is characterized by a single translocation involving the NUTM1 (NUT midline carcinoma family member 1) gene and different partner genes. The resulting fusion proteins initiate tumorigenesis through a mechanism involving BET (bromo-domain and extra-terminal motif) proteins such as Bromodomain-containing protein 4 (BRD4) and inordinate acetylation of chromatin, leading to the dysregulation of growth and differentiation genes. While no clinical characteristics are specific for NC, some histologic features can be indicative; therefore, patients with these tumor characteristics should be routinely tested for NUTM1. The diagnosis of NC using immunohistochemistry with a highly specific antibody is straightforward. There are currently no standard-of-care treatment options for patients with NC. However, novel therapies specifically addressing the unique tumorigenic mechanism are under investigation, including BET inhibitors. This review aims to raise awareness of this underdiagnosed cancer entity and provide all patients the opportunity to be properly diagnosed and referred to a clinical study.

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

“…With the increased understanding of tumor types that are regulated by BET/Brd4-associated oncogenes [ 46 , 47 ] and those driven by the Brd4 fusion [ 48 , 49 ], there has been enormous interest in developing novel BET inhibitors for cancer treatment. A number of the novel candidates are currently progressing through early clinical trials.…”

“…The BRD4–NUTM1 fusion protein was known to tether NUTM1 to acetylated chromatin via the Brd4 bromodomains. Subsequently, NUTM1 recruited the histone acetyltransferase EP300 to increase the acetylation of the surrounding chromatin to create a highly acetylated mega-domain, where proliferation genes (such as MYC and TP63 ) are induced to promote cancer proliferation [ 48 ]. Owing to the hallmark NUTM1 rearrangement of NC, diagnosis is usually made by immunohistochemical staining that recognizes the NUTM1 protein in the tumor tissue.…”

NUT carcinoma in pediatric patients: Characteristics, therapeutic regimens, and outcomes of 11 cases registered with the German Registry for Rare Pediatric Tumors (STEP)

“…[9][10][11] However, using a simple immunohistochemistry employing a highly specific anti-NUTM1-antibody makes the diagnosis quite easy and straightforward. 12 NC can occur at any age, from infants (even neonates) to elderly people; however, most cases are found in adolescents and young adults. 1,2 Cure or long-term survival is rare and mostly associated with the onset of tumor resections at localized disease stages; in adults, non-BRD4-fusions are also reported to be associated with better outcomes.…”

Immunodetection of NUT Protein: Implementation, Indications, and Results in a Tertiary Reference Center

“…2 Since the initial description, the clinical spectrum has progressively expanded: the possible occurrence in older patients and in many sites of the body has been recognized. 1,3 The pathologic spectrum also expanded, with the identification of other subsets of NUTM1-rearranged tumors, some of which raise nosological issues or problems of differential diagnosis. 4 Finally, in addition to the prototypical translocation NUTM1::BRD4, other partners can be involved and their number is increasing.…”

“…4 Finally, in addition to the prototypical translocation NUTM1::BRD4, other partners can be involved and their number is increasing. 3 Despite the progress in the understanding and diagnosis of NUT carcinoma, its prognosis remains very poor, despite the possible emergence of targeted therapies, currently under evaluation. 3 The histopathologic diagnosis of NUT carcinoma remains often difficult, especially in the absence of an appropriate clinical context: the morphologic and immunohistochemical features are variable, often not suggestive, and sometimes even misleading.…”