Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15as a novel mutation associated with metastasis

Autor: Xu, Shiqiong, Moss, Tyler J., Laura Rubin, Maria, Ning, Jing, Eterovic, Karina, Yu, Hong, Jia, Renbing, Fan, Xianqun, Tetzlaff, Michael T., Esmaeli, Bita
Zdroj: Modern Pathology; July 2020, Vol. 33 Issue: 7 p1256-1263, 8p
Abstrakt: Ocular adnexal sebaceous carcinoma (OASeC) is an aggressive eyelid carcinoma. Analysis of molecular-genetic drivers of this disease could reveal new prognostic markers and actionable targets for treatment. To identify somatically acquired genomic mutations in OASeC and explore their associations with metastasis, whole-exome sequencing on DNA extracted from retrospectively collected tumor samples was performed. Thirty-one patients in two orbital oncology centers with OASeC were included. Sequencing results were analyzed to detect mutations and explore their possible association with metastasis. The median patient age was 64 years. A total of 1780 candidate somatic mutations were identified with median mutation rate of 1.0/Mb (range, 0.2–13.6). The five most commonly mutated genes (as determined by MutSig; qvalue < 0.25) were TP53(mutated in 22 cases), ZNF750(13 cases), RB1(12 cases), NOTCH1(8 cases), and PCDH15(5 cases). Mutations in ZNF750or NOTCH1pathway genes were present in 24 (77%) of the 31 cases; there was a trend toward mutual exclusivity of ZNF750and NOTCH1mutations. All eight tumors with NOTCH1mutations also had TP53and/or RB1mutations. Four of the five PCDH15mutations and all four PCDH15missense mutations were identified in patients with metastatic disease, including one patient with distant metastasis and three with nodal metastasis. PCDH15was significantly associated with metastasis (P= 0.01). We identified the most commonly mutated genes in a series of OASeCs and found a previously unreported mutation in OASeC, PCDH15mutation, that was significantly associated with metastasis. NOTCH1mutation is an actionable mutation; clinical trials targeting this mutation are available throughout the US and could be considered for patients with metastatic NOTCH1-mutant OASeC. TP53, ZNF750, RB1, and PCDH15mutations are most likely loss-of-function mutations and may have diagnostic and prognostic importance.
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