Anti-RB1 monoclonal antibody, clone Sc2 2G9

Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant inRB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of theRB1transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is similar to 3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations inTP53, SMAD4, FGFR3, andMSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that anRB1leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.

There is minimal evidence of EGFR-mutated lung adenocarcinoma transforming to small cell lung carcinoma (SCLC) without the administration of EGFR-tyrosine kinase inhibitor (TKI). Here, we present a case of EGFR/PTEN co-mutated lung adenocarcinoma with lymph node metastases, which comprised adenocarcinoma admixed with SCLC. EGFR L858R and PTEN R130Q mutations were shared between the primary tumor and lymph node metastasis. Additionally, EGFR I744M mutation was shared between the adenocarcinoma and SCLC components in the lymph node metastasis, confirming spontaneous transformation from adenocarcinoma to SCLC. Furthermore, TP53 and RB1 mutations were detected only in the SCLC components of the lymph node metastasis. Immunohistochemically, complete absence of Rb expression in SCLC was observed, suggesting the loss of function of RB1. Our case clearly shows that EGFR/PTEN co-mutated lung adenocarcinoma transformed to SCLC in the lymph node without TKI-mediated evolutionary selection pressures.