Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The development of meningioma in NBCCS patients is a rare event. Here, we report two cases of NBCCS in which meningiomas did develop. The first patient carried a germline mutation in one allele of PTCH1, c.290dupA (p.N97KfsX43). In addition, the meningioma sample carried a somatic mutation, c.307delG (p.Val103LeufsX15), in the other allele of the same gene, suggesting a second hit. This is the first case of NBCCS-associated meningioma explained by the standard two-hit hypothesis. The second patient had a germline nonsense mutation in the SUFU gene, c.550C>T (p.Q184X). SUFU is located downstream of PTCH1 in the sonic hedgehog signaling pathway. This is the second time a germline mutation in SUFU has been found to cause NBCCS. Together with the previous report describing three cases of non-NBCCS medulloblastoma carrying a germline mutation in this gene, individuals with a SUFU germline mutation are expected to have a markedly high risk of developing medulloblastoma and probably meningioma.

Case Report Multiple nevoid basal cell carcinoma syndrome associated with congenital orbital teratoma, caused by a PTCH1 frameshift mutation

“…Although no founder mutation has been described in the literature, 2 specific mutations in different exons have been reported (Chidambaram et al, 1996;Wicking et al, 1997;Boutet et al, 2003;Ponti et al, 2012). The c.290dupA mutation identified in this Azorean patient is recurrent, as it was also recently described in a Japanese patient with multiple BCCs, jaw OKCs, calcification of the falx cerebri, and a meningioma at the age of 66 years (Kijima et al, 2012). These 2 patients had a different clinical outcome, indicating the involvement of modifier genes that are distinct from the disease locus, as identified for instance in neurofibromatosis type 1 (Bahuau et al, 2001;Ponti et al, 2011), or may have occurred because of different genetic backgrounds (Sunyaev, 2012).…”

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

“…As expected, Sufu-depleted Xenopus embryos develop severely reduced eyes (Min et al, 2011). In humans, inherited and sporadic mutations in SUFU have been identified in a wide variety of cancers, including medulloblastoma (Taylor et al, 2002;Brugieres et al, 2010), meningioma (Aavikko et al, 2012) and basal cell carcinoma (Pastorino et al, 2009;Kijima et al, 2012;Schulman et al, 2015). Interestingly, in contrast to Sufu in other vertebrate species, zebrafish Sufu is a weak Hh inhibitor, and knockdown of Sufu causes only a marginal increase in Hh signaling during zebrafish embryonic development (Wolff et al, 2003).…”

“…Loss of Sufu elevates vertebrate Hh signaling and induces severe patterning defects during development (Wolff et al, 2003;Cooper et al, 2005;Svard et al, 2006;Min et al, 2011). In humans, oncogenic mutations in SUFU have been identified from medulloblastoma, basal cell carcinoma and other cancers (Taylor et al, 2002;Pastorino et al, 2009;Brugieres et al, 2010;Aavikko et al, 2012;Kijima et al, 2012;Schulman et al, 2015). Despite the fundamental roles played by Sufu in development and cancer, it is largely unclear how the Sufu protein itself is regulated.…”

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…Importantly, heterozygous loss of Sufu, in conjunction with the loss of p53, leads to the development of medulloblastoma and rhabdomyosarcoma (Lee et al , 2007). Germline Sufu mutations have been identified in medulloblastoma (Taylor et al , 2002; Kool et al , 2014) and associated with the development of medulloblastoma in Gorlin syndrome (Pastorino et al , 2009; Kijima et al , 2012; Smith et al , 2014). Furthermore, somatic Sufu mutations have been identified in multiple other malignancies, including prostate cancer (Sheng et al , 2004).…”