In-silico analysis to identify the role of MEN1 missense mutations in breast cancer

Background: The multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 encodes menin protein. Previously reported mutations were thought to result in loss of function of menin protein and that they are associated with multiple endocrine neoplasia 1 disorder. However, recently menin has also been characterized as an oncosuppressor protein and it was suggested that mutations in it are associated with various other tumors. Studies indicate that the menin protein stimulates the estrogen receptor (ER) that in turn increases the predisposition for inherited breast cancer. Methods: Here, we used our supervised in-house combinatory in-silico predictor method to investigate the impact of unclassified missense mutations in MEN1 gene found in breast cancer tissue. We also examined the biophysical and biochemical properties to predict the effects of these missense variants on the menin protein stability and interactions. The results are compared with the effects of known pathogenic mutations in menin causing neoplasia. Results: Our analysis indicates that some of the variants found in breast cancer tissue show similar pattern of destabilizing the menin protein and its interactions as the pathogenic variants associated with neoplasia. Taking together with the results of our in-silico consensus predictor, we classify missense mutations in menin protein found in breast cancer tissue into pathogenic and benign, and thus, suggesting as an indicator for early detection of elevated breast cancer risk.

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Identification of Novel Variants in MEN1: A Study Conducted with Four Multiple Endocrine Neoplasia Type 1 Patients

Hormone and Metabolic Research ◽

10.1055/a-1147-1375 ◽

2020 ◽

Vol 52 (11) ◽

pp. 788-795

Author(s):

Wen-mu Hu ◽

Qin Zhang ◽

Li-hua Huang ◽

Zhao-hui Mo ◽

Xiao-dan Long ◽

...

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Genetic Characteristics ◽

Germline Variants ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Novel Variants ◽

The Impact

AbstractMultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited endocrine tumor syndrome caused by inactivating variants of the MEN1 gene. The aim of this study is to explore the clinical and genetic characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1 patients. All exons of the MEN1 and CDNK1B genes and adjacent exon-intron sequences were amplified by polymerase chain reaction and subsequently sequenced. Further, the splice alterations were studied by sequencing the amplified RT-PCR products for MEN1 cDNA. We identified four heterozygous MEN1 germline variants: c.564delC, c.1268G>A, IVS5+5delG, and c.1546_1547insC. Both c.564delC and IVS5+5delG were novel variants. The impact of the MEN1 splice variant, IVS5+5delG, was evaluated using bioinformatics and in vitro analyses. The analyses indicated that this variant resulted in skipping of the neighboring exon and was disease-causing. Two novel somatic variants, c.249_252delGTCT and c.313_314insC, were found. Additionally, loss of heterozygosity (LOH) for the MEN1 locus (IVS5+5delG and c.564delC) was found in tumor tissue samples from the MEN1 patients, consistent with Knudson’s two-hit mechanism. We identified four MEN1 germline variants and two novel somatic variants. Early recognition of the phenotype coupled with variant screening of the MEN1 gene is the key to diagnosing and treating MEN1 effectively at an early stage.

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Clinical and pre-clinical studies of neuroendocrine tumours (NETs) in multiple endocrine neoplasia type 1 (MEN1), and evaluation of MEN1 gene replacement therapy for MEN1-associated NETs

Endocrine Abstracts ◽

10.1530/endoabs.31.yep1.1 ◽

2013 ◽

pp. 1-1

Author(s):

Gerard Walls ◽

Paul Newey ◽

Manuel Lemos ◽

Mahsa Javid ◽

Sian Piret ◽

...

Keyword(s):

Replacement Therapy ◽

Clinical Studies ◽

Multiple Endocrine Neoplasia ◽

Neuroendocrine Tumours ◽

Multiple Endocrine Neoplasia Type ◽

Gene Replacement ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Gene Replacement Therapy

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Breast Cancer Tissue Bioreactor for Direct Interrogation and Observation of Response to Antitumor Therapies

10.21236/ada552540 ◽

2011 ◽

Author(s):

Lisa McCawley

Keyword(s):

Breast Cancer ◽

Breast Cancer Tissue ◽

Cancer Tissue

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Classifying Breast Cancer Tissue by Raman Spectroscopy with One-dimensional Convolutional Neural Network

Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy ◽

10.1016/j.saa.2021.119732 ◽

2021 ◽

pp. 119732

Author(s):

Danying Ma ◽

Linwei Shang ◽

Jinlan Tang ◽

Yilin Bao ◽

Juanjuan Fu ◽

...

Keyword(s):

Breast Cancer ◽

Neural Network ◽

Raman Spectroscopy ◽

Convolutional Neural Network ◽

Breast Cancer Tissue ◽

Cancer Tissue ◽

One Dimensional

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Indication of high lipid content in epithelial-mesenchymal transitions of breast tissues

Scientific Reports ◽

10.1038/s41598-021-81426-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Siti Norbaini Sabtu ◽

S. F. Abdul Sani ◽

L. M. Looi ◽

S. F. Chiew ◽

Dharini Pathmanathan ◽

...

Keyword(s):

Breast Cancer ◽

Raman Spectroscopy ◽

Multivariate Analysis ◽

Nucleic Acids ◽

Raman Spectra ◽

Cancer Progression ◽

Component Analysis ◽

Breast Cancer Tissue ◽

Metabolic Changes ◽

Cancer Tissue

AbstractThe epithelial-mesenchymal transition (EMT) is a crucial process in cancer progression and metastasis. Study of metabolic changes during the EMT process is important in seeking to understand the biochemical changes associated with cancer progression, not least in scoping for therapeutic strategies aimed at targeting EMT. Due to the potential for high sensitivity and specificity, Raman spectroscopy was used here to study the metabolic changes associated with EMT in human breast cancer tissue. For Raman spectroscopy measurements, tissue from 23 patients were collected, comprising non-lesional, EMT and non-EMT formalin-fixed and paraffin embedded breast cancer samples. Analysis was made in the fingerprint Raman spectra region (600–1800 cm−1) best associated with cancer progression biochemical changes in lipid, protein and nucleic acids. The ANOVA test followed by the Tukey’s multiple comparisons test were conducted to see if there existed differences between non-lesional, EMT and non-EMT breast tissue for Raman spectroscopy measurements. Results revealed that significant differences were evident in terms of intensity between the non-lesional and EMT samples, as well as the EMT and non-EMT samples. Multivariate analysis involving independent component analysis, Principal component analysis and non-negative least square were used to analyse the Raman spectra data. The results show significant differences between EMT and non-EMT cancers in lipid, protein, and nucleic acids. This study demonstrated the capability of Raman spectroscopy supported by multivariate analysis in analysing metabolic changes in EMT breast cancer tissue.

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Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22147352 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7352

Author(s):

Francesca Marini ◽

Maria Luisa Brandi

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Current Knowledge ◽

Neuroendocrine Cells ◽

Molecular Therapy ◽

Multiple Cancer ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited multiple cancer syndrome of neuroendocrine tissues. Tumors are caused by an inherited germinal heterozygote inactivating mutation of the MEN1 tumor suppressor gene, followed by a somatic loss of heterozygosity (LOH) of the MEN1 gene in target neuroendocrine cells, mainly at parathyroids, pancreas islets, and anterior pituitary. Over 1,500 different germline and somatic mutations of the MEN1 gene have been identified, but the syndrome is completely missing a direct genotype-phenotype correlation, thus supporting the hypothesis that exogenous and endogenous factors, other than MEN1 specific mutation, are involved in MEN1 tumorigenesis and definition of individual clinical phenotype. Epigenetic factors, such as microRNAs (miRNAs), are strongly suspected to have a role in MEN1 tumor initiation and development. Recently, a direct autoregulatory network between miR-24, MEN1 mRNA, and menin was demonstrated in parathyroids and endocrine pancreas, showing a miR-24-induced silencing of menin expression that could have a key role in initiation of tumors in MEN1-target neuroendocrine cells. Here, we review the current knowledge on the post-transcriptional regulation of MEN1 and menin expression by miR-24, and its possible direct role in MEN1 syndrome, describing the possibility and the potential approaches to target and silence this miRNA, to permit the correct expression of the wild type menin, and thereby prevent the development of cancers in the target tissues.

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Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)

Acta Endocrinologica ◽

10.1530/eje.0.1410475 ◽

1999 ◽

pp. 475-480 ◽

Cited By ~ 28

Author(s):

N Hai ◽

N Aoki ◽

A Matsuda ◽

T Mori ◽

S Kosugi

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Family Members ◽

Premature Stop Codon ◽

Germline Mutations ◽

Endocrine Tumors ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine tumors involving the parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in families with MEN1. DESIGN: Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. METHODS: Full-length sequencing of the open reading frame and exon-intron boundaries in the MEN1 gene was performed with probands of familial MEN1. Family members were examined for the identified mutation in the proband. RESULTS: We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectability of MEN1 mutations in familial MEN1 among studies that examined more than 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carriers in the course of the present study in those families. CONCLUSIONS: Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members of MEN1, should be considered as a standard procedure and categorized as belonging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.

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