Expression Analysis of Genes Involved in DNA Repair or Synthesis in Mixed Neuroendocrine/Nonneuroendocrine Carcinomas

Abstract

Background: Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome. Methods: Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas. Results: The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death. Conclusions: Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors.

Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms

“…For instance, the molecular study of 867 PDNEC of various origins showed that CDKN2A/B and APC mutations were present in 27 and 3% of pancreatic PDNEC (28.3 and 2.5% in pancreatic adenocarcinomas [78] ), respectively, compared to 6 and 47% of colon PDNEC (9.8 and 49.3% in colon adenocarcinomas [78] ), respectively [79] . In addition, 10-15% of PDNEC and MiNEN originating from colon, rectum, or stomach have a mismatch repair-deficient phenotype [21,24,75,80] . These neoplasms have an increased methylation profile and prolonged survival, similar to what is observed in elderly patients with sporadic colorectal adenocarcinoma and mismatch repair deficiency due to the methylation of promoter of specific genes, which supports a common carcinogenic pathway between PDNEC/ MiNEN and adenocarcinoma.…”

“…Surgical resection of localized pancreatic MiNEN containing acinar-cell carcinoma might improve survival [50,63,66] . The potential benefit of adjuvant treatments following resection of localized MiNEN is still undefined, although some retrospective data have suggested a favourable effect [24,30,38,39,68,85] .…”

“…The first-intent treatment of an advanced disease should include systemic chemotherapy combining etoposide and a platinum salt by analogy with PDNEC, and notably because the expression of ERCC1 (protein repairing the DNA damages caused by platinum salts) may be stronger in MiNEN than in adenocarcinoma of same location [24] . Upon progression, the first-line etoposideplatinum regimen could be reintroduced if this disease is controlled without chemotherapy for >3 months [84] .…”

“…Highgrade MiNEN generally combine a non-neuroendocrine carcinoma (usually adenocarcinoma, but possibly squamous-cell carcinoma or acinar-cell carcinoma in the pancreas as mentioned above) or an adenoma (villous or tubulo-villous) with a PDNEC component, which is generally more aggressive [20][21][22][23][24] . The prognosis of intermediate-grade MiNEN is generally determined by the non-neuroendocrine component rather than the G1 or G2 NET component.…”

Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

“…A benefit in metastatic Merkel cell carcinoma was also seen for another anti-PD-L1 antibody, i.e., avelumab [62]. As GEP NEC has a high mutational burden, immunotherapy could be of value for many NEC patients [20,[63][64][65]. Several immunotherapy trials are ongoing in G3 patients.…”