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Comparative genomics of high grade neuroendocrine carcinoma of the cervix.

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.

SUBMITTER: Hillman RT

PROVIDER: S-EPMC7297329 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Comparative genomics of high grade neuroendocrine carcinoma of the cervix.

Hillman R Tyler RT Cardnell Robert R Fujimoto Junya J Lee Won-Chul WC Zhang Jianjun J Byers Lauren A LA Ramalingam Preetha P Leitao Mario M Swisher Elizabeth E Futreal P Andrew PA Frumovitz Michael M

PloS one 20200616 6

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 muta ...[more]

PMID: 32544169

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Project description:Background: In 2015, large cell neuroendocrine carcinoma (LCNEC) was removed from the large cell carcinoma group and classified with small cell lung carcinoma (SCLC) constituting two members of the high-grade neuroendocrine tumors (NETs) of the lung. However, the difference between high-grade LCNEC and SCLC in terms of clinicopathological characteristics and prognosis has not been fully understood owing to the rarity of LCNEC. Patients and methods: Patients with high-grade LCNEC and SCLC at initial diagnosis between 2001 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) program database. Clinicopathological characteristics between high-grade LCNEC and SCLC were compared using the Pearson's chi-squared test or Fisher's exact test. Differences in overall survival (OS) and cancer-specific survival (CSS) were compared using the log-rank test, Cox models and propensity score matching (PSM) analysis. Results: A total of 1223 patients with high-grade LCNEC and 18182 patients with high-grade SCLC were enrolled. To the best of our knowledge, this study involved the largest number of high-grade LCNEC patients to date, with respect to a comparison between high-grade LCNEC and high-grade SCLC patients. There were significant differences in age, sex, race, laterality, SEER stage, nodal status, surgery, radiation and chemotherapy, but not marital status, between high-grade LCNEC and SCLC patients. High-grade LCNEC patients had a better OS and CSS than high-grade SCLC patients. Subgroup analysis also confirmed the better prognosis of the high-grade LCNEC patients in the regional stage, distant stage and surgery subgroups. However, no significant difference in prognosis was observed between the two non-surgery subgroups, which was confirmed using PSM analysis. Furthermore, high-grade LCNEC patients showed different metastatic patterns to high-grade SCLC patients. Conclusion: These results suggested that high-grade LCNEC and high-grade SCLC were different histological types, and that a detailed classification for high-grade NETs of the lung was needed.

Project description:BackgroundNeuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials.MethodsWe performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC.ResultsThree thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports.ConclusionNECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

Dataset Information

Comparative genomics of high grade neuroendocrine carcinoma of the cervix.

Publications

Comparative genomics of high grade neuroendocrine carcinoma of the cervix.

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