【佳學(xué)基因靶向藥物基因檢測(cè)】繪制與肝內(nèi)膽管癌中可操作驅(qū)動(dòng)因素相關(guān)的共突變模式

千萬(wàn)不要做檢測(cè)基因合理嗎

挖掘基因組組學(xué)個(gè)性化藥物選擇記錄《J Hepatol》在 2022 Dec 15;S0168-8278(22)03328-1.發(fā)表了一篇題目為《Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Gajanan Kendre, Karthikeyan Murugesan, Tilman Brummer, Oreste Segatto, Anna Saborowski, Arndt Vogel等完成。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)了基因信息檢測(cè)與分析的重要性。 這項(xiàng)研究對(duì)腫瘤診斷和治療有以下幾點(diǎn)重要意義: 通過(guò)分析大樣本數(shù)據(jù)集,深入洞察了膽管細(xì)胞性肝內(nèi)膽管癌(iCCA)的分子亞組特點(diǎn)和基因組異質(zhì)性,有助于這種罕見(jiàn)癌癥的正確診療。 該研究對(duì)iCCA中7種重要致癌驅(qū)動(dòng)基因的共突變譜進(jìn)行了詳細(xì)分析,這對(duì)開(kāi)發(fā)相關(guān)的靶向治療策略具有指導(dǎo)意義。 發(fā)現(xiàn)負(fù)選擇規(guī)律的存在,如RTK/RAS/ERK通路的共突變,為臨床用藥提供了依據(jù)。 識(shí)別了一些特定亞組如MSI高和TMB高的特征突變,可作為這些腫瘤的生物標(biāo)志物。 這項(xiàng)研究結(jié)果可為iCCA相關(guān)的臨床試驗(yàn)設(shè)計(jì)、動(dòng)物模型建立、耐藥機(jī)制研究等提供參考,推動(dòng)iCCA正確醫(yī)療的發(fā)展。 強(qiáng)調(diào)了進(jìn)行腫瘤分子檢測(cè)的必要性,指導(dǎo)個(gè)體化的靶向治療策略。 提供了一個(gè)可參考的iCCA基因組數(shù)據(jù)庫(kù),有利于這類罕見(jiàn)癌癥研究的開(kāi)展。 總體來(lái)說(shuō),這項(xiàng)研究豐富了iCCA的基因組特征數(shù)據(jù),有助于發(fā)展診斷標(biāo)志物和正確治療策略,對(duì)改善這種腫瘤的臨床結(jié)果具有積極意義。

腫瘤基因檢測(cè)及靶向藥物治療研究關(guān)鍵詞：

膽道癌,基因組改變,免疫療法,正確醫(yī)療,靶向治療。

腫瘤治療檢測(cè)基因臨床應(yīng)用結(jié)果

背景與目的：近年來(lái)，肝內(nèi)膽管癌 (iCCA) 已發(fā)展成為胃腸道癌癥正確腫瘤學(xué)的“榜樣”。然而，它的稀有性及其基因組異質(zhì)性對(duì)靶向治療的發(fā)展和演變提出了挑戰(zhàn)。詢問(wèn)大型數(shù)據(jù)集有助于更好地了解罕見(jiàn)癌癥分子亞組的特征，并能夠識(shí)別在較小隊(duì)列中仍未被識(shí)別的基因組模式。佳學(xué)基因解碼的途徑：我們對(duì) FoundationCORE 數(shù)據(jù)庫(kù)中診斷為 iCCA 的 6,130 名接受診斷面板的患者進(jìn)行了回顧性分析FoundationOne 平臺(tái)上的測(cè)序。評(píng)估了超過(guò) 300 個(gè)腫瘤相關(guān)基因的短變異/融合重排和拷貝數(shù)改變，并且大多數(shù)隊(duì)列的腫瘤突變負(fù)荷 (TMB) 以及微衛(wèi)星不穩(wěn)定性 (MSI) 狀態(tài)可用。靶向藥物研究的客觀數(shù)據(jù)：我們提供 iCCA 基因組景觀的高度代表性制圖，并概述七個(gè)治療相關(guān)的致癌驅(qū)動(dòng)基因的共突變譜：IDH1/2、FGFR2、ERBB2、BRAF、MDM2、BRCA1/2、MET 和 KRASG12C。我們觀察到 RTK/RAS/ERK 通路共同改變的負(fù)選擇，以及 IDH1/2 和 FGFR2 改變患者中表觀遺傳修飾因子（如 ARID1A 和 BAP1）的富集。 RNF43 以及 KMT2D 在 MSIhigh 和 TMBhigh 腫瘤中以高頻率發(fā)生。藥物指導(dǎo)及病因判斷的依據(jù)：對(duì)最普遍的基因組星座的詳細(xì)了解是制定 iCCA 有效治療策略的關(guān)鍵。我們的研究提供了寶貴的資源，可用于評(píng)估臨床試驗(yàn)和亞組分析的可行性，促進(jìn)轉(zhuǎn)化相關(guān)臨床前模型的發(fā)展，并作為知識(shí)庫(kù)來(lái)預(yù)測(cè)基因組定義的亞組中靶向治療的潛在耐藥機(jī)制。影響和意義：由于可靶向改變的頻率很高，建議對(duì)膽道癌患者進(jìn)行分子診斷，尤其是 iCCA 患者。然而，可操作病變的識(shí)別并不能保證治療成功，并且共突變譜可能作為藥物反應(yīng)的關(guān)鍵調(diào)節(jié)劑。使用來(lái)自 6,130 名 iCCA 患者的綜合面板測(cè)序結(jié)果的大型數(shù)據(jù)集，我們提供了最常見(jiàn)的藥物基因改變的共突變譜的詳細(xì)分析，旨在作為建立遺傳相關(guān)臨床前模型的參考，開(kāi)發(fā)假設(shè)驅(qū)動(dòng)的聯(lián)合療法并確定反復(fù)性遺傳特征。關(guān)鍵詞：膽道癌；基因組改變；免疫療法；正確醫(yī)療；靶向治療。

腫瘤發(fā)生與革命國(guó)際數(shù)據(jù)庫(kù)描述：

Background & aims: In recent years, intrahepatic cholangiocarcinoma (iCCA) has evolved as a "role model" for precision oncology in gastrointestinal cancers. However, its rarity, paired with its genomic heterogeneity, challenges the development and evolution of targeted therapies. Interrogating large datasets drives better understanding of the characteristics of molecular subgroups of rare cancers and enables the identification of genomic patterns that remain unrecognized in smaller cohorts.Methods: We performed a retrospective analysis of 6,130 patients diagnosed with iCCA from the FoundationCORE database who received diagnostic panel sequencing on the FoundationOne platform. Short variants/fusion-rearrangements and copy number alterations in >300 tumor-associated genes were evaluated, and the tumor mutational burden (TMB) as well as the microsatellite instability (MSI) status were available for the majority of the cohort.Results: We provide a highly representative cartography of the genomic landscape of iCCA and outline the co-mutational spectra of seven therapeutically relevant oncogenic driver genes: IDH1/2, FGFR2, ERBB2, BRAF, MDM2, BRCA1/2, MET and KRASG12C. We observed a negative selection of RTK/RAS/ERK pathway co-alterations, and an enrichment of epigenetic modifiers such as ARID1A and BAP1 in patients with IDH1/2 and FGFR2 alterations. RNF43 as well as KMT2D occurred with high frequency in MSIhigh and TMBhigh tumors.Conclusion: Detailed knowledge of the most prevalent genomic constellations is key to the development of effective treatment strategies for iCCA. Our study provides a valuable resource that could be used to assess the feasibility of clinical trials and subgroup analyses, spurs the development of translationally relevant preclinical models, and serves as a knowledge base to predict potential mechanisms of resistance to targeted therapies in genomically defined subgroups.Impact and implications: Due to the high frequency of targetable alterations, molecular diagnostics is recommended in patients with biliary tract cancers, and especially in those with iCCA. The identification of an actionable lesion, however, does not guarantee therapeutic success, and the co-mutational spectrum may act as a critical modifier of drug response. Using a large dataset of comprehensive panel sequencing results from 6,130 patients with iCCA, we provide a detailed analysis of the co-mutational spectrum of the most frequent druggable genetic alterations, which is meant to serve as a reference to establish genetically relevant preclinical models, develop hypothesis-driven combination therapies and identify recurrent genetic profiles.Keywords: biliary tract cancer; genomic alterations; immunotherapy; precision medicine; targeted therapy.

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