Predictive role of CCND1, FGFR1 gene amplifications and PIK3CA mutations for endocrine therapy of primary metastatic breast cancer

Background. More than half of breast carcinomas express estrogen and progesterone receptors (ER and PR) and remain estrogen-dependent. Endocrine therapy with inhibitors of the estrogen cascade allows long-term and effective control of the disease in a significant number of patients, however, some patients demonstrate primary, and the majority - secondary resistance to such treatment. The aim of the study was to evaluate the predictive significance of the CCND1 and FGFR1 gene amplifications and PIK3CA mutations for endocrine therapy. Materials and methods. The study included 138 women with ER-positive primary metastatic breast cancer (BC) who received hormone therapy with aromatase inhibitors (AIs) (n = 69), tamoxifen (n = 65), goserelin (n = 2), or a combination of goserelin and tamoxifen (n = 2) as the first line treatment. CCND1 and FGFR1 gene amplifications were tested by digital droplet PCR, while mutations in exons 7, 9, and 20 of the PIK3CA gene were determined using high-resolution melting analysis and allele-specific PCR. We analyzed the associations between the presence of the mentioned genetic lesions, progression-free-survival (PFS) and response to treatment. Results. Amplifications of CCND1 and FGFR1 genes were identified in 24 (17.9%) and 28 (20.9%) of 134 successfully tested cases, respectively; 9 tumors were positive for both alterations. Amplifications were more prevalent in less differentiated tumors (p = 0.018). CCND1 amplification was associated with shorter PFS in patients receiving aromatase inhibitors (16.0 months vs. 32.4 months, HR = 3.16 [95% CI: 1.26-7.93], p = 0.014). FGFR1 status did not significantly affect PFS of AI-treated women, however, partial regress as a result of AI implementation was less frequent in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number (p = 0.031). The frequency of PIK3CA mutations was 40.2% (49/122). They were more often observed in smaller tumors (p = 0.034), in PR-positive carcinomas (p = 0.012), and in cases with more extensive metastatic involvement (p = 0.029). The presence of PIK3CA mutations did not affect the results of treatment with AI or tamoxifen. Conclusion The presence of CCND1 and/or FGFR1 amplification is associated with worse results of AI therapy of metastatic breast cancer.

Novel Mutations in FGFR1 Causing Idiopathic Hypogonadotropic Hypogonadism: A Cohort Study in Eastern Indian Population

Introduction: IHH is a clinically and genetically heterogeneous condition with more than 80 different mutations described in literature, some of the important being KAL-1 (anosmin), fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor-8 (FGF8). Objective: To characterize the clinical findings and molecular analysis of FGFR1 (KAL2) genes in 10 unrelated patients of idiopathic hypogonadotropic hypogonadism with and without hyposmia/anosmia. Methods: After confirming the diagnosis of IHH from detailed history, clinical and biochemical examination the patients were subjected to MRI of pituitary hypothalamic area and olfactory bulb and tract. For genetic analysis PCR of 18 exons was performed on the genomic DNA. The PCR products were purified, sequenced and analysed using BLAST search from NCBI GenBank. Results: We diagnosed ten unrelated sporadic cases of IHH (9 male and 1 female). Out of 10 cases 6 (60%) had anosmia (KS) 4 had normosmia. A variable degree of pubertal development was observed, including various clinical abnormalities, such as micropenis, dental agenesis, skeletal deformity, seizure disorder and bimanual synkinesis. All the patients who had anosmia (KS) had either hypoplasia or aplasia of olfactory bulb and tract on MRI. Two KS patients had novel sporadic FGFR1 mutation, one had a mutation n.2370 C>A detected at exon 10 of FGFR1 gene and another had a mutation n.1875 GA>CA at exon 8C of FGFR1 gene. Discussion: Loss-of-function sequence variants in FGFR1, encoding the fibroblast growth factor receptor-1, account for one autosomal dominant form of KS. Pathogenic changes in KAL1 or FGFR1 have been detected in approximately 20% of the KS patients, which indicates that other responsible genes are still to be discovered. FGFR1 comprises an extracellular region consisting of three immunoglobulin-like domains (D1-D3), a single transmembrane helix, and an intracellular region containing the tyrosine kinase domain. D2, D3 and the short linker between them house all the determinants of ligand (FGF) binding and specificity. In addition, alternative splicing of exon 8, encoding the D3 C-terminal half, leads to two FGFR1 isoforms, FGFR1b (exon 8A) and FGFR1c (exon 8B), with different specificities towards FGF ligands. All the pathogenic changes in FGFR1 that have been reported in KS so far disrupt both isoforms of FGFR1 i.e. FGF1b and FGF1c, therefore leaving open the question of which isoform(s) is (are) required in the olfactory bulb morphogenetic process. We identified a new mutation in exon 8C (patient no 2). Conclusions: IHH and KS patients present with broad spectrum of clinical manifestations. We identified two novel mutations in FGFR1 gene in two unrelated sporadic cases of KS in the Indian population.

The Role of The ?klotho Gene, Fgf21 and Fgfr1 in Cancerogenesis

Klotho was discovered in 1997 as an anti-aging gene that, when overexpressed, may extend the life span, but when it is disrupted, it may be a factor responsible for premature aging syndrome. The structure and the role of αKlotho and βKlotho genes from Klotho family in malignant tumors is described. The expression profile of the βKlotho gene is significantly different from the expression of the αKlotho gene. Analysis of Klotho expression in breast cancer, cervical cancer as well as endometrial cancer are discussed. The available data indicate the involvement of βKlotho in the neoplastic transformation of the endometrium. More advanced disease is related to negative expression of βKlotho gene. Fibroblast growth factors (FGFs) are a large family of proteins characterized by different functions in the cell development and metabolism. The FGF signaling is also associated with cancerogenesis. The relation between some FGF subfamilies and endometrial cancer clinical data is reported. The interaction between FGF subfamilies and the Klotho subfamily proteins acting as a co-receptor is stressed. Disorders in signaling of the FGF / FGFR pathway have been confirmed in gynecology. It can be assumed that increased expression of FGF21 might be a suppressor factor in endometrial cancer. The FGF21 factor, like the βKlotho protein, achieves its biological effect via the FGFR1 receptor. High expression of the FGFR1 gene inhibits further tumor growth. FGFR1 has the potential to perform both a suppressor and promoter role in the oncogenesis process.

Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia

Key Points A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.

Clinical, hematological and cytogenetic profile in fibroblast growth factor receptor 1 rearranged hematoloymphoid malignancies

FGFR1 belongs to a family of four, high-affinity receptor tyrosine kinase and is a legitimate oncogene associated with uterine, cervical, prostate, bladder, colorectal and lung cancers. It is rarely concomitant in myeloid and lymphoid neoplasms but has an aggressive clinical course with a high mortality rate when present. Cytogenetic abnormalities involving the FGFR1 gene is most frequently observed in AML, MPN with eosinophilia, T-ALL and T-LBL with ZMYM2 gene being the most common fusion partner. Methods of this study was to authors report a series of 4 cases with FGFR1 rearrangements. Results is three patients presented as T-cell Lymphoblastic lymphoma (T-LBL) and one as mixed phenotype acute leukemia (MPAL). The T-LBL cases harbored the FGFR1/ ZMYM2 fusion and the MPAL case harbored the CNTRL/FGFR1 fusion as identified by conventional cytogenetics and confirmed by molecular studies. Conclusion is authors herewith describe the clinical, biochemical, molecular and cytogenetic features observed in these cases.