Nevoid Basal Cell Carcinoma Syndrome: PTCH1 Mutation Profile and Expression of Genes Involved in the Hedgehog Pathway in Argentinian Patients.

Maria Martinez,Fernando Stengel,Luis Mazzuoccolo,Maria Romano,Alfredo Martinez,Carolina Muchnik,Pablo Azurmendi,Abel González

doi:10.3390/cells8020144

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCC), mainly caused by PTCH1 gene mutations. Our current study aimed to establish (1) PTCH1 germinal and somatic mutational status, (2) component and Hedgehog (HH) pathway targets gene expression patterns, and (3) profile variations according to the genetic background in BCC and normal surrounding skin (NSS). We collected 23 blood and 20 BCC patient samples and analyzed the PTCH1 gene using bidirectional sequencing and multiplex ligation-dependent probe amplification. Quantitative PCR was used to determine the mRNA expression levels of PTCH1, SMO, GLI3, and CCND1 in paired samples of BCC and NSS from 20 patients and four non-NBCCS skin controls (C). Our analyses identified 12 germline and five somatic sequence variants in PTCH1. mRNA levels of PTCH1, SMO, and GLI3 were higher in NSS compared to C samples, reaching maximum values in BCC samples (p < 0.05). NSS with PTCH1 germline mutations had modified SMO, PTCH1, and GLI3 mRNA levels compared to samples without mutation (p < 0.01). Two PTCH1 mutations in BCC led to an increase in PTCH1, SMO, and GLI3, and a decrease in CCND1 mRNA levels (p < 0.01 vs. BCC with germline mutation only). These results indicate that besides PTCH1, other genes are responsible for NBCCS and BCC development in a population exposed to high UV radiation. Additionally, the mutational events caused increased expression of HH-related genes, even in phenotypically normal skin.

Highlights

Nevoid basal cell carcinoma syndrome (NBCCS; OMIM #109400)— known as the Gorlin–GoltzSyndrome—is a multisystem genetic disorder with an autosomal dominant inheritance pattern, Cells 2019, 8, 144; doi:10.3390/cells8020144 www.mdpi.com/journal/cellsCells 2019, 8, 144 complete penetrance, and variable expression [1]
This study provides a new mutational analysis of the PTCH1 gene, distinguished by its germinal and somatic status, and the Hedgehog pathway gene expression profile in Argentine patients with
We describe the largest Latin American cohort that belongs to a population exposed to larger UV radiation, due to its geographical location

Summary

Introduction

Nevoid basal cell carcinoma syndrome (NBCCS; OMIM #109400)— known as the Gorlin–GoltzSyndrome—is a multisystem genetic disorder with an autosomal dominant inheritance pattern, Cells 2019, 8, 144; doi:10.3390/cells8020144 www.mdpi.com/journal/cellsCells 2019, 8, 144 complete penetrance, and variable expression [1]. Nevoid basal cell carcinoma syndrome (NBCCS; OMIM #109400)— known as the Gorlin–Goltz. NBCCS patients are characterized by numerous malformations and a high susceptibility for developing multiple basal cell carcinomas (BCC)—the most common type of cancer worldwide—at an early age. PTCH1 is the human homolog of the Drosophila segment polarity gene, with 23 exons that encode a transmembrane glycoprotein composed of 1447 amino acids, and is responsible for most NBCCS cases. PTCH1 acts as a receptor in the Hedgehog signaling pathway [2,3]. Hedgehog (HH), are morphogens that physiologically drive the inhibitory signaling effects of PTCH1 over smoothened, which in turn activates the GLI effectors. GLI proteins are transcription factors that stimulate their target genes to induce cell cycle effects

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