A nonsense mutation in SUFU associated with multiple infundibulocystic basal cell carcinomas.

Dear Editors, Sporadic basal cell carcinoma (BCC) is caused by aberrations in the hedgehog (Hh) signaling pathway. Within this pathway, SUFU acts as a tumor suppressor. PTCH1 is mutated in 70% whereas SUFU is mutated in about 8% of BCCs.1 SUFU loss of heterozygosity (LOH) only leads to BCC, when additional mutations in tumor suppressor genes such as p53 or oncogenes such as PTCH1 are present.2 Although the majority of BCCs arises sporadically, genodermatoses such as basal cell nevus syndrome (BCNS), which is mostly caused by a mutation in PTCH1 and SMO, can also lead to BCC formation.3 Requena et al. first described an autosomal dominant genodermatosis characterized by various infundibulocystic BCCs, a rare and more indolent subtype, and was therefore termed multiple hereditary infundibluocystic BCC syndrome (MHIBCC).4 Schulman et al. later associated MHIBCC with a proposed germline SUFU mutation that was found in five tumor samples and in normal mucosal tissue of the patient.5 These previously described MHIBCC cases showed multiple well-differentiated, indolent, and mostly infundibulocystic basal cell carcinomas on the face and genitals, but no other characteristics of basal cell nevus syndrome. We report on a 65-year-old woman with more than 40 histologically confirmed BCCs (Figure 1). Family history was negative for BCC and medulloblastoma. Our patient reported no prior brain abnormalities (shown in a recent MRI), no further comorbidities, no signs of immunosuppression, no occupational risk factors, no prior cancers (including no prior therapy with ionizing irradiation) and no signs of other cancer prone syndromes. Additionally, no sun sensitivity was reported. However, occasional sunbathing and use of tanning beds in early adulthood were reported. The majority (> 30) of tumors were found on her face but BCCs formed at atypical sites, including her left palm (Figure 2c), groin (Figure 2b), and the outer edge of the left foot (Figure 2d) as well. Clinical examination also showed multiple skin-colored papules on the face (Figure 2a), which developed in her adult life and had been histologically diagnosed as sebaceous hyperplasia. Germline mutation screening was performed by targeted next generation sequencing with a four gene panel including the full coding sequence of PTCH1, BAP1, FLCN and SUFU (NM_016169.3). Samples were sequenced with an Illumina MiSeq (Illumina, San Diego, CA, USA). A heterozygous nonsense mutation in exon 4 was detected in the SUFU gene (c.595C>T), which led to a stop signal on codon 199 (p.Gln199Stop). This nonsense mutation is located on the N-terminal domain of the protein and might cause a nonsense-mediated mRNA decay or at least results in a truncated protein. The variant has not yet been described, but loss of function mutations in the tumor suppressor gene SUFU are known to cause BCNS. This is of particular importance for the usage of Hh-inhibitors in patients with advanced or metastatic BCC. While SUFU mutations confer resistance to such treatment, tumors with an additional or sole aberration in PTCH1 are likely sensitive to Hh-inhibitors.6 Genetic analysis of three BCCs and two sebaceous hyperplasias using a commercial NGS panel (targeted panel sequencing using the Oncomine Comprehensive Assay v3, ThermoFisher) was performed. Libraries were sequenced on the Ion GeneStudio S5 Plus platform and analyzed with Torrent Suite and Ion Reporter Software (ThermoFisher) (Supplementary Table S1). Neither sebaceous hyperplasia showed any likely pathogenic or pathogenic mutations. However, the BCC on the foot yielded PTCH1 (likely pathogenic) and TP53 (pathogenic) missense mutations while two BCCs on the face showed no relevant aberration in PTCH1 or other genes analyzed. Interestingly, two BCCs (foot, face) showed missense mutations in both the oncogene KNSTRN and the tumor suppressor gene ATRX. Three of four point mutations affecting the ATRX and KNSTRN gene were not characterized biologically and were therefore categorized as variant of unknown significance (VUS).7 The p.Ser24Phe mutation in KNSTRN was described as likely pathogenic/likely loss of function according to OncoKB. A detailed overview of all pathogenic/likely pathogenic variants and VUS is shown in Supplementary Table S1. We present a patient with MHIBCC harboring a nonsense germline mutation in SUFU. So far, no truncating SUFU variants associated with MHIBCC have been described. Germline mutations in SUFU have mostly been associated with pediatric medulloblastoma,8 while they are rarely found in patients with BCNS.9 Both KNSTRN and ATRX encode for proteins involved in chromosomal regulation. Chromosome dysfunction due to mutations in KNSTRN and ATRX likely causes chromosomal instability and promotes oncogenesis. The oncogene KNSTRN has previously been associated with early stage (<2 cm in size) BCC.10 Tumor suppressor ATRX has been described in the context of glioma development,11 which is, like BCC, associated with SUFU mutations. The yet unclear interactions between SUFU and ATRX might help understand the concurrent evolution of both glioma and BCC in BCNS patients. We conclude that the patient's germline mutation in SUFU led to the formation of multiple infundibulocystic BCCs. Our data indicate that the emergence of BCCs in MIHBB at atypical sites such as groin, palm, and foot might be associated with additional mutations in oncogenes and/or tumor suppressors. Open access funding enabled and organized by Projekt DEAL. None.