Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development. OBJECTIVE: To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS. RESULTS: We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. CONCLUSIONS: Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.

Load-bearing capacity of CAD/CAM 3D-printed zirconia, CAD/CAM milled zirconia, and heat-pressed lithium disilicate ultra-thin occlusal veneers on molars.

OBJECTIVES: The load-bearing capacity of ultra-thin occlusal veneers made of 3D-printed zirconia were compared to the ones obtained by fabricating these reconstructions by CAD/CAM milling zirconia or heat-pressing lithium-disilicate. METHODS: On 60 extracted human molars, the occlusal enamel was removed and extended into dentin. Occlusal veneers of 0.5 mm thickness were digitally designed. The specimens were divided into 3 groups (n = 20 each) differing in the restorative material and the fabrication technique of the occlusal veneer. (1) 3DP: 3D-printed zirconia (Lithoz); (2): CAM: milled zirconia (Ceramill Zolid FX); (3) HPR: heat-pressed lithium disilicate (IPS e.max Press). After conditioning procedures, the restorations were adhesively bonded onto the conditioned tooth. Thereafter, all specimens were aged in a chewing simulator by exposure to cyclic fatigue and temperature variations. Subsequently the specimens were statically loaded and the load which was necessary to decrease the maximum load by 20% and initiate a crack (Finitial) and the load which was needed to fracture the specimen (Fmax) were measured. Differences between the groups were compared applying the Kruskal-Wallis (KW) test and the Wilcoxon-Mann-Whitney-Test (WMW: p < 0.05). RESULTS: The median Finitial values for the groups 3DP, CAM and HPR were 1'650 N, 1'250 N and 500 N. The differences between all three groups were statistically significant (KW: p < 0.0001). The median Fmax values amounted to 2'026 N for the group 3DP, 1'500 N for the group CAM and 1'555 N for the group HPR. Significant differences were found between 3DP and CAM (WMW: p = 0.0238). SIGNIFICANCE: Regarding their load-bearing capacity, 3D-printed or milled zirconia as well as heat-pressed lithium disilicate can be recommended as restorative material for ultra-thin occlusal veneers to prosthetically compensate for occlusal tooth wear. Despite statistically significant differences between the restoration materials, all load-bearing capacities exceeded the clinically expected normal bite forces.