scholarly journals Genetic Alterations in Invasive Breast Carcinoma with a Glycogen-Rich Clear Cell Pattern: A Case Report

2021 ◽  
pp. 500-505
Author(s):  
Carlo De la Sancha ◽  
Roberto Ruiz-Cordero ◽  
Nikolay Popnikolov
Keyword(s):  
Breast Carcinoma ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Invasive Breast Carcinoma ◽  
Molecular Characteristics ◽  
Dna Breaks ◽  
Cell Pattern ◽  
Truncating Mutation

Invasive carcinoma with a glycogen-rich clear cell pattern (IC-GRCCP) is a rare and understudied subtype of invasive breast carcinoma of no special type (IBC-NST). Here we report the molecular characteristics of a mammary IC-GRCCP diagnosed in a 69-year-old woman. Next-generation sequencing of the tumor revealed an inv(1)(p36.12,q32.1) leading to loss-of-function of ARID1A gene, a MAP2K4 truncating mutation (p.E376), MYC amplification, a variant of uncertain significance of PTPRB gene (p.D1848N) and deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A. The analysis of the involved pathways shows close resemblance to the ovarian clear cell carcinoma and indicates similarities in the molecular mechanisms of development of glycogen-rich clear cell carcinomas in different organs. Our findings and the literature review suggest new potential strategies for treatment of mammary IC-GRCCP, including epigenetic therapies, checkpoint inhibitors, radiation, or other double-strand DNA breaks-inducing agents. Nevertheless, larger studies are needed to substantiate those ideas.

Loss-Of-Function Mutation Of ARID1A Tumor Suppressor Gene In A Glycogen-Rich Clear Cell Mammary Carcinoma

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S146-S146
Author(s):  
C A De la Sancha Verduzco ◽  
N Popnikolov ◽  
R Ruiz-Cordero
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Chromosome 1 ◽  
Loss Of Function ◽  
Truncating Mutation ◽  
Molecular Studies

Abstract Introduction/Objective Glycogen-rich clear cell carcinoma (GRCC-CA) is a rare subtype of breast carcinoma accounting for 0.9 - 3% of all breast malignancies. It is characterized by more than 90% of the neoplastic cells containing glycogen-abundant clear cytoplasm. Due to the rarity of this tumor, the information about the specific genetic alterations, their prognostic significance and potential therapeutic implications are quite limited. Here we report the molecular alterations of a GRCC-CA diagnosed in a 69-year-old woman. Methods Tumor-only sequencing using a hybrid-capture next-generation sequencing (HC-NGS) assay was performed using formalin-fixed paraffin-embedded tissue. The HC-NGS panel included the coding regions of 479 cancer-related genes, select introns of 47 genes and the TERT promoter. Results The HC-NGS showed the following alterations: 1) large inversion in chromosome 1 between exon 20 of gene ARID1A (1p36.12) and intron 2 of KDM5B (1q32.1) leading to loss-of-function of ARID1A tumor suppressor gene, 2) MAP2K4 p.E376 truncating mutation with a variant allelic frequency of 87% suggestive of loss-of-heterozygosity, 3) c- MYC gene amplification (5x), 4) variant of uncertain significance in gene PTPRB (p.D1848N) and 5) deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A genes. Conclusion We report for the first time a loss-of-function mutation of ARID1A gene in mammary GRCC-CA. Loss of function of ARID1A gene, as shown by molecular studies or loss of protein expression, is often seen in clear cell carcinomas with high glycogen contents from other sites (ovary and kidney), indicating similarities in the molecular mechanisms of development. In our patient, the loss of ARID1A probably enhanced the effect of the c-MYC amplification, since ARID1A is involved in the repression of c-MYC and other proliferation associated genes during differentiation. Larger molecular studies are needed to elucidate further the genetic mechanisms of mammary GRCC- CA.

scholarly journals Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1570 ◽  
Author(s):  
Lum ◽  
Alamgeer
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Small Cell ◽  
Endobronchial Ultrasound ◽  
Cell Renewal ◽  
Small Cell Lung

Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient derived xenografts (PDXs) have made encouraging inroads. Whole genome sequencing (WGS) data reveals a high mutational burden and a number of genetic alterations but low frequency of targetable mutations. Despite several failures, considerable therapeutic opportunities have recently emerged. Potentially promising therapies include those targeting DNA damage repair, stem cell/renewal and drug resistant mechanisms. Modest success has also been achieved with immune checkpoint inhibitors while therapeutic exploration of various other components of the immune system is underway. However, the complex heterogeneities reflect the need for accurate bio-markers to translate novel discoveries into clinical benefit. Additionally, the molecular mechanisms that differentiate chemo-sensitive from chemo-refractory disease remain unknown. Obtaining reliable tumour samples by utilising novel techniques such as endobronchial ultrasound guided needle aspiration or adopting to liquid biopsies are becoming popular. This review will focus on recent technological and therapeutic advancements to surmount this recalcitrant disease.

scholarly journals Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5981
Author(s):  
Pablo Álvarez Ballesteros ◽  
Jesús Chamorro ◽  
María San Román-Gil ◽  
Javier Pozas ◽  
Victoria Gómez Dos Santos ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

scholarly journals Classification of clear cell renal cell carcinoma based on PKM alternative splicing

2019 ◽  
Author(s):  
Xiangyu Li ◽  
Beste Turanli ◽  
Kajetan Juszczak ◽  
Woonghee Kim ◽  
Muhammad Arif ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Drug Repositioning ◽  
Expression Profiles ◽  
Molecular Characteristics ◽  
Cell Renal Cell Carcinoma ◽  
Histologic Heterogeneity

SummaryClear cell renal cell carcinoma (ccRCC) accounts for 70–80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.

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