Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma – a case report

Abstract Background Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research. Case presentation We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH. Conclusion Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.

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Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms23010251 ◽

2021 ◽

Vol 23 (1) ◽

pp. 251

Author(s):

Inmaculada Ribera-Cortada ◽

José Guerrero-Pineda ◽

Isabel Trias ◽

Luis Veloza ◽

Adriana Garcia ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Copy Number ◽

Large Scale ◽

Somatic Mutations ◽

Genetic Alterations ◽

Copy Number Alterations ◽

Hpv Status ◽

Penile Squamous Cell Carcinoma

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

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Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype

Communications Biology ◽

10.1038/s42003-020-01175-x ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Benjamin S. Simpson ◽

Niedzica Camacho ◽

Hayley J. Luxton ◽

Hayley Pye ◽

Ron Finn ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Large Scale ◽

Genetic Alterations ◽

Gleason Grade ◽

Copy Number Alterations ◽

Aggressive Prostate Cancer ◽

Prostate Cancer Development ◽

Transcriptional Changes ◽

Cancer Phenotype

AbstractLarge-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited. Germline SNPs in the 3q26.31 locus are associated with aggressive prostate cancer, and is the location of NAALADL2, a gene overexpressed in aggressive disease. The closest gene to NAALADL2 is TBL1XR1, which is implicated in tumour development and progression. Using publicly-available cancer genomic data we report that NAALADL2 and TBL1XR1 gains/amplifications are more prevalent in aggressive sub-types of prostate cancer when compared to primary cohorts. In primary disease, gains/amplifications occurred in 15.99% (95% CI: 13.02–18.95) and 14.96% (95% CI: 12.08–17.84%) for NAALADL2 and TBL1XR1 respectively, increasing in frequency in higher Gleason grade and stage tumours. Gains/amplifications result in transcriptional changes and the development of a pro-proliferative and aggressive phenotype. These results support a pivotal role for copy-number gains in this genetic region.

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Copy Number Alterations of PAX5, CDKN2A/B Genes Rather Than IKZF1 gene Are Associated with Pathogenesis of Childhood ALL in Korean Assessed by Multiplex Ligation-Dependent Probe Amplification

Blood ◽

10.1182/blood.v118.21.4231.4231 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4231-4231

Author(s):

Dong Kyun Han ◽

Li Yu ◽

Huong Thi Thanh Tran ◽

Hee Nam Kim ◽

Il Kwon Lee ◽

...

Keyword(s):

Cell Cycle ◽

Copy Number ◽

Cell Cycle Control ◽

Genetic Alterations ◽

Prognostic Impact ◽

Reference Ranges ◽

Copy Number Alterations ◽

Childhood All ◽

Korean Children ◽

Dependent Probe

Abstract Abstract 4231 Background: Recent genomic studies have analyzed genetic alterations and gene expression in childhood acute lymphoblastic leukemia (ALL), and detected multiple new submicroscopic genetic abnormalities in key cellular pathways, and also identified new prognostic markers and therapeutic targets. More than 50 recurring genetic alterations have been identified, and these genes are known to play key or putative roles in lymphoid development and leukemogenesis. Multiplex Ligation-dependent Probe Amplification (MLPA) is a rapid multiplex PCR based technique that allows the comparative quantification of multiple sites. However, there have been no reports on the MLPA based copy number alterations (CNA) of childhood ALL in Asian countries. The aim of this study is to reveal the CNA of genes involved in lymphoid differentiation and cell cycle control in Korean children with ALL. Patients and Methods: Reference ranges for individual MLPA probes were established from a group of 30 healthy control subjects. The MLPA assay was performed for 121 children with ALL in Korea to target those genes including the lymphoid differentiation genes (BTG1, EBF1, IKZF1, and PAX); cell cycle control genes (CDKN2A/B and RB1); transcriptional factors regulating genes (ETV6); and those deleted from the PAR1 region (IL3RA, CRLF2 and CSF2RA). We also evaluated the prognostic impact of these abnormalities. Results: Out of the 121 patients analyzed in our study, 96 (79%) displayed CNA in at least one gene: PAX5, 49 (40%); CDKN2A, 42 (35%); CDKN2B, 35 (29%); IKZF1, 22 (18%); ETV6, 22 (18%); EBF1, 16 (13%); RB1, 16 (13%); BTG1, 14 (12%); CRLF2, 12 (10%); IL3RA, 12 (10%); CSF2RA, 11 (9%). Thirteen of 121 (11%) patients relapsed. There was no significant correlation between these CNA and the recurrence of ALL. Conclusion: These results suggest that CNA of PAX5, CDKN2A/B may play an important role in the pathogenesis of childhood ALL in Korea, contrasting to those findings from western countries showing a significant correlation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other possible genes are warranted in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

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EPCO-29. EPIGENOMICS OF THE GLIOMA LONGITUDINAL ANALYSIS (GLASS) CONSORTIUM

Neuro-Oncology ◽

10.1093/neuonc/noaa215.308 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii75-ii75

Author(s):

Thais Sabedot ◽

Michael Wells ◽

Indrani Datta ◽

Tathiane Malta ◽

Ana Valeria Castro ◽

...

Keyword(s):

Dna Methylation ◽

Longitudinal Analysis ◽

Copy Number ◽

Large Scale ◽

Molecular Classification ◽

Tumor Burden ◽

Copy Number Alterations ◽

Unsupervised Analysis ◽

Diffuse Gliomas ◽

New Biomarkers

Abstract Adult diffuse gliomas are central nervous system (CNS) tumors that arise from the malignant transformation of glial cells. Nearly all gliomas will recur despite standard treatment however, current histopathological grading fails to predict which of them will relapse and/or progress. The Glioma Longitudinal AnalySiS (GLASS) consortium is a large-scale collaboration that aims to investigate the molecular profiling of matched primary and recurrent glioma samples from multiple institutions in order to better understand the dynamic evolution of these tumors. At this time, the cohort comprises 946 samples across 11 institutions and among those, 864 have DNA methylation data available. The current molecular classification based on 7 subtypes published by TCGA in 2016 was applied to the dataset. Among the IDH wildtype tumors, 33% (16/49) of the patients showed a change of subtype upon recurrence, whereas most of them (9/16) were Classic-like at the primary stage but changed to either Mesenchymal-like or PA-like at the recurrent level. Among the IDH mutant tumors, 15% (22/142) showed a change of subtype at recurrent stage, in which 16 out of 22 progressed from G-CIMP-high to G-CIMP-low. Although some tumors progressed to a different subtype upon recurrence, an unsupervised analysis showed that the samples tend to cluster by patient instead of by subtype. By estimating the copy number alterations of these tumors using DNA methylation, the overall copy number profile of the recurrent samples remains similar to their primary counterpart. From this initial analysis using epigenomic data, we were able to characterize some aspects of glioma evolution and how the DNA methylation is associated with the progression of these tumors to different subtypes. These findings corroborate the importance of epigenetics in gliomas and can potentially lead to the identification of new biomarkers that can reflect tumor burden and predict its development.

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PI-PLCβ1 gene copy number alterations in breast cancer

Oncology Reports ◽

10.3892/or.2011.1529 ◽

2011 ◽

Cited By ~ 1

Author(s):

Chiara Molinari

Keyword(s):

Breast Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Copy Number Alterations

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Next-Generation Sequencing–Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer

Journal of Molecular Diagnostics ◽

10.1016/j.jmoldx.2018.10.006 ◽

2019 ◽

Vol 21 (2) ◽

pp. 307-317 ◽

Cited By ~ 8

Author(s):

Sounak Gupta ◽

Chad M. Vanderbilt ◽

Paolo Cotzia ◽

Javier A. Arias-Stella ◽

Jason C. Chang ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Copy Number ◽

Copy Number Alterations ◽

Next Generation ◽

Generation Sequencing

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Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

Rhinology Journal ◽

10.4193/rhino15.382 ◽

2016 ◽

Vol 54 (3) ◽

pp. 278-286

Author(s):

J. Perez-Escuredo ◽

A. Lopez-Hernandez ◽

M. Costales ◽

F. Lopez ◽

S.P. Ares ◽

...

Keyword(s):

Clinical Outcome ◽

Copy Number ◽

Genetic Alterations ◽

Intestinal Type ◽

Dust Exposure ◽

Copy Number Alterations ◽

A Genome ◽

Sinonasal Adenocarcinoma ◽

Gains And Losses ◽

Microarray Cgh

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

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