Molecular testing in metastatic basal cell carcinoma

Background: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. Objective: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. Methods: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. Results: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. Limitations: In 2 patients there was insufficient qualitative DNA available for genetic analysis. Conclusions: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value

Lack of genotype-phenotype correlation in basal cell nevus syndrome:A Dutch multicenter retrospective cohort study

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A meta-analysis of genome-wide association studies identifies multiple longevity genes

Publisher's version (útgefin grein).Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.Alexander von Humboldt-StiftungPeer Reviewe

A meta-analysis of genome-wide association studies identifies multiple longevity genes

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity

Update on Hedgehog Pathway Inhibitor Therapy for Patients with Basal Cell Naevus Syndrome or High-frequency Basal Cell Carcinoma

Some patients with basal cell carcinoma develop a large number of basal cell carcinomas during their lives. The most common underlying genetic disease that causes multiple basal cell carcinomas is basal cell naevus syndrome. Basal cell naevus syndrome is caused by a germline mutation in patched-1 (PTCH1), a tumour suppressor gene of the hedgehog signalling pathway. However, in a significant portion of patients with multiple basal cell carcinomas, no underlying genetic cause is found. Nevertheless, these patients can experience a treatment burden comparable to that of patients with basal cell naevus syndrome. They are referred to as high-frequency basal cell carcinoma patients. Hedgehog pathway inhibitors were the first group of targeted therapy for basal cell carcinomas. This study reviews the literature on hedgehog pathway inhibitor therapy for patients with basal cell naevus syndrome or high-frequency basal cell carcinoma, to provide an overview on efficacy, safety, dosing regimens, tumour resistance and reoccurrence, and health-related quality of life

New mutations and an updated database for the patched-1 (PTCH1) gene

Background: Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched-1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly. Methods: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). We included 117 new PTCH1 variations, in addition to 331 previously published unique PTCH1 mutations. These new mutations were found in 141 patients who had a positive PTCH1 mutation analysis in either the VU University Medical Centre (VUMC) or Maastricht University Medical Centre (MUMC) between 1995 and 2015. Results: The database contains 331 previously published unique PTCH1 mutations and 117 new PTCH1 variations. Conclusion: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). The database provides an open collection for both clinicians and researchers and is accessible online at http://www.lovd.nl/PTCH1

Molecular testing in metastatic basal cell carcinoma

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. OBJECTIVE: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. METHODS: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. RESULTS: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. LIMITATIONS: In 2 patients there was insufficient qualitative DNA available for genetic analysis. CONCLUSIONS: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value