Molecular Basis of Cisplatin Resistance in Testicular Germ Cell Tumors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064173%3A_____%2F19%3AN0000017" target="_blank" >RIV/00064173:_____/19:N0000017 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/19:10398957 RIV/00216208:11110/19:10398957 RIV/00216208:11120/19:43918741 RIV/00216208:11130/19:10398957 RIV/00064190:_____/19:N0000036

Result on the web

<a href="https://doi.org/10.3390/cancers11091316" target="_blank" >https://doi.org/10.3390/cancers11091316</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers11091316" target="_blank" >10.3390/cancers11091316</a>

Result language

angličtina

Original language name

Molecular Basis of Cisplatin Resistance in Testicular Germ Cell Tumors

Original language description

The emergence of cisplatin (CDDP) resistance is the main cause of treatment failure and death in patients with testicular germ cell tumors (TGCT), but its biologic background is poorly understood. To study the molecular basis of CDDP resistance in TGCT we prepared and sequenced CDDP-exposed TGCT cell lines as well as 31 primary patients' samples. Long-term exposure to CDDP increased the CDDP resistance 10 times in the NCCIT cell line, while no major resistance was achieved in Tera-2. Development of CDDP resistance was accompanied by changes in the cell cycle (increase in G1 and decrease in S-fraction), increased number of acquired mutations, of which 3 were present within ATRX gene, as well as changes in gene expression pattern. Copy number variation analysis showed, apart from obligatory gain of 12p, several other large-scale gains (chr 1, 17, 20, 21) and losses (chr X), with additional more CNVs found in CDDP-resistant cells (e.g., further losses on chr 1, 4, 18, and gain on chr 8). In the patients' samples, those who developed CDDP resistance and died of TGCT (2/31) showed high numbers of acquired aberrations, both SNPs and CNVs, and harbored mutations in genes potentially relevant to TGCT development (e.g., TRERF1 , TFAP2C in one patient, MAP2K1 and NSD1 in another one). Among all primary tumor samples, the most commonly mutated gene was NSD1 , affected in 9/31 patients. This gene encoding histone methyl transferase was also downregulated and identified among the 50 most differentially expressed genes in CDDP-resistant NCCIT cell line. Interestingly, 2/31 TGCT patients harbored mutations in the ATRX gene encoding a chromatin modifier that has been shown to have a critical function in sexual differentiation. Our research newly highlights its probable involvement also in testicular tumors. Both findings support the emerging role of altered epigenetic gene regulation in TGCT and CDDP resistance development.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/LO1604" target="_blank" >LO1604: CLIP Leukemia: cell analysis 2.0</a><br>

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cancers

ISSN

2072-6694

e-ISSN

—

Volume of the periodical

11

Issue of the periodical within the volume

9

Country of publishing house

CH - SWITZERLAND

Number of pages

18

Pages from-to

1316

UT code for WoS article

000489719000101

EID of the result in the Scopus database

2-s2.0-85073518336