Targeted panel sequencing of pharmacogenes and oncodrivers in colorectal cancer patients reveals genes with prognostic significance

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11140%2F24%3A10482129" target="_blank" >RIV/00216208:11140/24:10482129 - isvavai.cz</a>

Alternative codes found

RIV/75010330:_____/24:00014715 RIV/00669806:_____/24:10482129

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4msP3n_v6u" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4msP3n_v6u</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s40246-024-00644-2" target="_blank" >10.1186/s40246-024-00644-2</a>

Result language

angličtina

Original language name

Targeted panel sequencing of pharmacogenes and oncodrivers in colorectal cancer patients reveals genes with prognostic significance

Original language description

BACKGROUND: Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy. RESULTS: The median number of detected variants per tumor sample was 18.5 with 4 classified as having a high predicted functional effect and 14.5 moderate effect. APC, TP53, and KRAS were the most frequent mutated genes (64%, 59%, and 42% of mutated samples, respectively) followed by FAT4 (23%), FBXW7, and PIK3CA (16% for both). Patients with advanced stage III had more frequently APC, TP53, or KRAS mutations than those in stages I or II. KRAS mutation counts followed an increasing trend with grade (G1 &lt; G2 &lt; G3). The response to adjuvant therapy was worse in carriers of frameshift mutations in APC or 12D variant in KRAS, but none of these oncodrivers had prognostic value. Carriage of somatic mutations in any of the genes ABCA13, ANK2, COL7A1, NAV3, or UNC80 had prognostic relevance for worse overall survival (OS) of all patients. In contrast, mutations in FLG, GLI3, or UNC80 were prognostic in the same direction for patients untreated, and mutations in COL6A3, LRP1B, NAV3, RYR1, RYR3, TCHH, or TENM4 for patients treated with adjuvant therapy. The first association was externally validated. From all germline variants with high or moderate predicted functional effects (median 326 per patient), &gt; 5% frequency and positive Manhattan plot based on 3-year RFS, rs72753407 in NFACS, rs34621071 in ERBB4, and rs2444274 in RIF1 were significantly associated with RFS, OS or both. CONCLUSIONS: The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.

Czech name

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Czech description

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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

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2024

Confidentiality

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

Name of the periodical

Human Genomics

ISSN

1473-9542

e-ISSN

1479-7364

Volume of the periodical

18

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

15

Pages from-to

83

UT code for WoS article

001272959600001

EID of the result in the Scopus database

2-s2.0-85199042865