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Viral neuro-oncogenesis: Polyomaviruses and brain tumors
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Martyn K. White, Sidney E. Croul, Kamel Khalili
The occurrence of medulloblastomas in identical twins was first noted by Harvey Cushing and reported by Leavitt. Since that time, other familial clusters have also been noted to involve dizygotic twins and siblings [105–107]. Associated tumors include Wilms’s tumor and malignant rhabdoid tumor. A small number of medulloblastomas are associated with the heritable Gorlin and Turcot syndromes. Gorlin or basal cell nevus syndrome is an autosomal dominant disorder characterized by multiple developmental defects and susceptibility to cancers including medulloblastoma [108–110]. The defective gene is a human homolog of Drosophila patched in the hedgehog (Hh)/PTCH pathway. Examination of sporadic medulloblastomas has also revealed loss of heterozygosity and somatic mutations of the human PTCH allele in 15%–20% of tumors [111,112]. In Turcot syndrome, mutations of the APC gene of the Wingless pathway lead to colonic tumors and brain tumors including medulloblastomas [113].
Cancer of the Ovary
Published in Jennifer L. Kelsey, Nancy G. Hildreth, Breast and Gynecologic Cancer Epidemiology, 2019
Jennifer L. Kelsey, Nancy G. Hildreth
It has been established that three rare genetic syndromes, the Peutz-Jeghers syndrome, the basal cell nevus syndrome, and gonadal dysgenesis, predispose to ovarian tumors. The Peutz-Jeghers syndrome, which is characterized by mucotaneous pigmentation and gastrointestinal polyposis, is associated particularly with tumors of the granulosa cell type.105–108 The ovarian tumors often occur at a relatively young age. The reason for an increased incidence of ovarian tumors among women with this syndrome is unknown, but Christian106 has hypothesized that a common embryological defect may predispose to ovarian tumors and the Peutz-Jeghers syndrome. The basal cell nevus syndrome, a rare syndrome characterized by multiple basal cell tumors of the skin, cysts of the jaw, abnormalities of the ribs and metacarpal bones, and several endocrine abnormalities, is associated with benign ovarian fibromas.109,110 Individuals with dysgenetic gonads (phenotypic females who usually have a karyotype of 46 XY or 45 XO/ 46 XY) are prone to have a distinctive type of benign ovarian tumor called a gonado-blastoma.111–118 First described by Scully,119 these tumors are composed of germ cells and immature Sertoli or granulosa cells and have been found to occur almost exclusively in individuals with dysgenetic gonads. These tumors occur less often among individuals with Turner’s syndrome than among those with pure gonadal dysgenesis.111,118
Pathogenesis of Odontogenic Cysts
Published in Roger M. Browne, Investigative Pathology of the Odontogenic Cysts, 2019
If the initiation of cyst formation is genetically determined, it is not known whether the abnormality is acquired or hereditarily transmitted and whether it affects the epithelium or the cells of the cyst capsule. A heredity transmission is suggested by the evidence previously quoted of a peak incidence in the second and third decades and an association with the basal cell nevus syndrome. However, odontogenic keratocysts are diagnosed in patients up to the ninth decade of life and several studies have demonstrated a second peak of incidence in the fifth or sixth decade,13,17,23,65–67 which suggests an acquired abnormality may also play a role. This bimodal age distribution may indeed indicate two distinct groups of patients who suffer from this condition. The views have been expressed that odontogenic keratocysts are either hamartomas1 or benign cystic neoplasms,14,68 although the evidence for both points of view is equivocal. The possible neoplastic nature of these cysts is discussed further in Chapter 11.
Resistance to hedgehog inhibitors in basal cell carcinoma: strategies to adopt
Published in Expert Opinion on Drug Safety, 2022
Alessia Villani, Gabriella Fabbrocini, Francesc Di Vico, Francesca Nastro, Massimiliano Scalvenzi
To Editor: Although surgery still represents the gold-standard treatment for the majority of basal cell carcinomas (BCCs), patients presenting with advanced BCCs, locally advanced (la) or metastatic (m) ones, not amenable with surgery or radiation therapy always require different therapeutic options [1]. Most of BCCs are characterized by an aberrant activation of the Hedgehog signaling pathway, in particular, an inactivating mutation of patched homologue 1 (PTCH1) gene, or, less often an activating mutation of Smoothened homologue (SMO) gene, leading to hedgehog signaling pathway dysregulation and consequently to the activation of GLI gene transcription, thus resulting in tumor cells differentiation and proliferation. To date, vismodegib and sonidegib are the only SMO-inhibitors FDA- and EMA-approved for the treatment of adult patients with advanced BCCs following surgery or radiotherapy or for those who are not candidates for surgery or radiation therapy [2,3]. SMO-inhibitors have also represented a valid therapeutic option in some cases of basal cell nevus syndrome, or Gorlin syndrome, in those forms associated with PTCH1 mutation; although several clinical studies have shown the efficacy and safety of vismodegib and sonidegib in treating advanced BCCs, cases of resistance to treatment due to SUFU mutations, which are downstream to SMO have been reported [4]. We read with great interest the report [5] written in response to our article entitled ‘Expert opinion on sonidegib efficacy, safety and tolerability’[6], describing genetic alterations occurring downstream of the hedgehog inhibitor target, thus conferring resistance to SMO-inhibitors.
Genetic alterations conferring resistance to hedgehog inhibitors in basal cell carcinoma
Published in Expert Opinion on Drug Safety, 2022
Basal cell nevus syndrome, or Gorlin syndrome (GS), is due to mutations within the Hh pathway, and patients with GS typically present with multiple, and in some cases, more than 100 BCCs at the time of presentation [3]. GS most commonly involves mutations in PTCH1, but SUFU mutations may occur as well [3,4]. For these patients, it is difficult to surgically remove each BCC, and radiation therapy may be associated with a number of adverse effects, including cognitive deficit and seizure disorder [3]. Thus, SMO inhibitors are an appealing option for GS. While the use of SMO inhibitors may be effective for PTCH-1 associated GS, it is not effective for SUFU-associated GS because SUFU is downstream SMO in the Hh pathway [3–5]. Furthermore, infundibulocystic BCC is a subtype of BCC histologically distinguished by dermal proliferation of anastomosing cords and strands of basoloid cells with associated small infundibular-type, keratin-filled cysts [6]. Reports have noted SUFU mutations, which are downstream of SMO, in patients with infundibulocystic BCC [5,6]; therefore, this type of variant of BCC may be a clue to Hh inhibitor resistance. A case of infundibulocystic BCC with SUFU mutation showed no response to daily vismodegib treatment [5]. Thus, a potential challenge in the treatment of advanced BCCs with SMO inhibitors is resistance due to mutations downstream of SMO in the Hh pathway. Furthermore, inhibiting the Hh pathway in these resistant cases was also associated with considerable adverse effects [4,5]. Genetic testing of tumors may be indicated in cases of advanced BCC or infundibulocystic BCC to ensure that the existing Hh mutation occurs upstream of SMO to avoid unnecessary adverse effects of vismodegib or sonidegib [5].
Nevoid basal cell carcinoma syndrome: a case report and literature review
Published in Ophthalmic Genetics, 2022
Shripadh Chitta, Jineet Patel, Shravan Renapurkar, Christopher Loschiavo, Jennifer Rhodes, Kayla King, Kimberly Salkey, Natario Couser
Nevoid basal cell carcinoma syndrome (NBCCS, OMIM #109400) is a rare autosomal dominant disorder first classified by Dr. Gorlin and Dr. Goltz in 1960 in a family that presented with clinical manifestations of basal cell carcinomas, bifid ribs, and jaw cysts(1). By the end of the 20th century, several studies would further characterize the condition as one involving a number of developmental pathologies and tumors identified via clinical and radiological evaluation (2,3). The disorder has had multiple names over the years including but not limited to “Gorlin syndrome,” “Gorlin-Goltz syndrome,” “basal cell nevus syndrome,” and “multiple nevoid basal-cell carcinoma syndrome.”