Potential for clinical management of pancreatic cancer through whole exome profiling of site-specific metastases and matched primary tumors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11140%2F25%3A10498978" target="_blank" >RIV/00216208:11140/25:10498978 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15110/25:73634564 RIV/00098892:_____/25:10159331 RIV/00669806:_____/25:10498978 RIV/75010330:_____/25:00015027

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=MuFhDzxj2S" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=MuFhDzxj2S</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.labinv.2025.104205" target="_blank" >10.1016/j.labinv.2025.104205</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Potential for clinical management of pancreatic cancer through whole exome profiling of site-specific metastases and matched primary tumors

Popis výsledku v původním jazyce

Considering the lack of molecular background of the metastatic process in pancreatic ductal adenocarcinoma (PDAC) and fact that the location of the metastasis may carry prognostic information and potential therapeutic opportunities, we aimed to explore genomic profiles of metastases from diverse loci and their value for the patients&apos; therapeutic management. DNA samples from paired primary and metastatic tissue of 20 patients were microdissected and sequenced using whole exome target enrichment. Somatic genetic variability, copy number variations (CNVs), and mutational signatures were assessed for associations with clinical data of patients. KRAS (78% in primary tumors-74% in metastases), TP53 (67-68%), CDKN2A (28-37%), and SMAD4 (22-26%) were the most commonly mutated oncodrivers in primary tumors and metastases. Other frequently mutated genes were CCDC187 (50%-58%), MUC5AC (50%-53%), EPPK1 (39%-63%), SYN2 (39%-26%), MUC19 (33%-47%), MUC3A (33%-26%), DNAH12 (28%-37%), ZBED3 (22%-26%), PKHD1L1 (28%-16%), and GTPBP6 (11%-32%). Lung metastases differed from other metastatic sites (liver, stomach, and locoregional) in a higher frequency of nonsense mutations in the MH2 domain of SMAD4, oncodriver co-mutations, gains on chromosomes 2 and 20, CNV counts, and share of signature SBS5. Somatic alterations of KRAS in metastases (p=0.041) and MUC3A in both loci (p=0.041 and p=0.011, respectively) and CNVs count and size in metastases (p=0.024 and p=0.011) associated with response to systemic chemotherapy. Patients with mutated KRAS (p=0.045), high mutational load (p=0.004), and frequent CNVs (p=0.004) in metastatic loci had shortened survival after metastasis resection. Interestingly, the personalized-treatment targetable alterations, such as microsatellite instability and mismatch repair or homologous recombination deficiencies did not differ between the primary tumors and paired metastases or between the metastases from different secondary sites and had no prognostic value. The results suggest a potential prognostic role of KRAS mutations, mutation load, and CNVs in PDAC patients after metastasectomy and encourage further molecular profiling for personalized treatment of PDAC patients with different metastasis localization.

Název v anglickém jazyce

Potential for clinical management of pancreatic cancer through whole exome profiling of site-specific metastases and matched primary tumors

Popis výsledku anglicky

Considering the lack of molecular background of the metastatic process in pancreatic ductal adenocarcinoma (PDAC) and fact that the location of the metastasis may carry prognostic information and potential therapeutic opportunities, we aimed to explore genomic profiles of metastases from diverse loci and their value for the patients&apos; therapeutic management. DNA samples from paired primary and metastatic tissue of 20 patients were microdissected and sequenced using whole exome target enrichment. Somatic genetic variability, copy number variations (CNVs), and mutational signatures were assessed for associations with clinical data of patients. KRAS (78% in primary tumors-74% in metastases), TP53 (67-68%), CDKN2A (28-37%), and SMAD4 (22-26%) were the most commonly mutated oncodrivers in primary tumors and metastases. Other frequently mutated genes were CCDC187 (50%-58%), MUC5AC (50%-53%), EPPK1 (39%-63%), SYN2 (39%-26%), MUC19 (33%-47%), MUC3A (33%-26%), DNAH12 (28%-37%), ZBED3 (22%-26%), PKHD1L1 (28%-16%), and GTPBP6 (11%-32%). Lung metastases differed from other metastatic sites (liver, stomach, and locoregional) in a higher frequency of nonsense mutations in the MH2 domain of SMAD4, oncodriver co-mutations, gains on chromosomes 2 and 20, CNV counts, and share of signature SBS5. Somatic alterations of KRAS in metastases (p=0.041) and MUC3A in both loci (p=0.041 and p=0.011, respectively) and CNVs count and size in metastases (p=0.024 and p=0.011) associated with response to systemic chemotherapy. Patients with mutated KRAS (p=0.045), high mutational load (p=0.004), and frequent CNVs (p=0.004) in metastatic loci had shortened survival after metastasis resection. Interestingly, the personalized-treatment targetable alterations, such as microsatellite instability and mismatch repair or homologous recombination deficiencies did not differ between the primary tumors and paired metastases or between the metastases from different secondary sites and had no prognostic value. The results suggest a potential prognostic role of KRAS mutations, mutation load, and CNVs in PDAC patients after metastasectomy and encourage further molecular profiling for personalized treatment of PDAC patients with different metastasis localization.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Laboratory Investigation

ISSN

0023-6837

e-ISSN

1530-0307

Svazek periodika

105

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

104205

Kód UT WoS článku

001540319300001

EID výsledku v databázi Scopus

2-s2.0-105010609282