Abstract
In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.
Highlights
High grade neuroendocrine cervical carcinoma (NECC) is a rare malignancy accounting for less than 1% of cervical cancers
One tumor (NECC013) exhibited a somatic mutation rate more than ten times the median for the cohort (Fig 1A), and this tumor contained a pathogenic MSH2 missense mutation (p.G164R) suggesting that defective DNA mismatch repair (MMR) may explain the hypermutation phenotype observed in this tumor sample
We found that NECC exhibits contributions from several previously defined mutagenic processes (Fig 4A), including large contributions from an age-related signature related to spontaneous deamination of 5-methylcytosine (Signature 1) and from activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) deaminase activity (COSMIC Signature 2 & Signature 13) [22,23]
Summary
High grade neuroendocrine cervical carcinoma (NECC) is a rare malignancy accounting for less than 1% of cervical cancers. The treatment of NECC has been influenced by current practices in the management of the more common cervical cancer histologies, as well as by treatment approaches to pulmonary small cell neuroendocrine carcinomas [3,4]. Small cell neuroendocrine malignancies can arise at many anatomic sites, including small cell neuroendocrine carcinomas of the lung (SCLC) and bladder (SCCB). These extra-cervical small cell carcinomas share features with NECC including small cell diameter, high nuclear/cytoplasmic ratio, and frequent necrosis. EP is frequently used for NECC, it is not known if this regimen is superior to alternative platinum-based regimens used in the treatment of advanced cervical cancer of other histologic subtypes [4]
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