来自具有致病性MUTYH和NTHL1双等位基因变异的个体的腺瘤显示出与结直肠癌相似的碱基切除修复肿瘤突变特征谱,扩大了潜在的诊断和变异分类应用。

IF 5 2区 医学 Q2 Medicine Translational Oncology Pub Date : 2025-02-01 DOI:10.1016/j.tranon.2024.102266
Romy Walker , Jihoon E. Joo , Khalid Mahmood , Mark Clendenning , Julia Como , Susan G. Preston , Sharelle Joseland , Bernard J. Pope , Ana B.D. Medeiros , Brenely V. Murillo , Nicholas Pachter , Kevin Sweet , Allan D. Spigelman , Alexandra Groves , Margaret Gleeson , Krzysztof Bernatowicz , Nicola Poplawski , Lesley Andrews , Emma Healey , Steven Gallinger , Peter Georgeson
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The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic <em>MUTYH</em> cases, on 7 adenomas and 2 CRCs from 5 biallelic <em>NTHL1</em> cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.</div></div><div><h3>Results</h3><div>In biallelic <em>MUTYH</em> cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, <em>p-value</em>=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, <em>p-value</em>=3.4 × 10<sup>–4</sup>). Similarly, in biallelic <em>NTHL1</em> cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, <em>p-value</em>=5.1 × 10<sup>–7</sup>). Additionally, a compound heterozygote with the c.1187G&gt;<em>A</em> p.(Gly396Asp) pathogenic variant and the c.533G&gt;C p.(Gly178Ala) variant of unknown significance (VUS) in <em>MUTYH</em> demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.</div></div><div><h3>Conclusions</h3><div>SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic <em>MUTYH</em> and biallelic <em>NTHL1</em> cases, respectively. 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Pope ,&nbsp;Ana B.D. Medeiros ,&nbsp;Brenely V. Murillo ,&nbsp;Nicholas Pachter ,&nbsp;Kevin Sweet ,&nbsp;Allan D. Spigelman ,&nbsp;Alexandra Groves ,&nbsp;Margaret Gleeson ,&nbsp;Krzysztof Bernatowicz ,&nbsp;Nicola Poplawski ,&nbsp;Lesley Andrews ,&nbsp;Emma Healey ,&nbsp;Steven Gallinger ,&nbsp;Peter Georgeson\",\"doi\":\"10.1016/j.tranon.2024.102266\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in <em>MUTYH</em> or <em>NTHL1</em> exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. 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引用次数: 0

摘要

背景:来自MUTYH或NTHL1双等位种系可能致病/致病变异的人群的结直肠癌(crc)表现出特异性的单碱基替代(SBS)突变特征,即SBS18和SBS36 (SBS18+SBS36)和SBS30的组合。目的是确定双等位病例的腺瘤是否在诊断水平上表现出这些突变特征。方法:对13例双等位基因MUTYH患者的9例腺瘤和15例crc、5例双等位基因NTHL1患者的7例腺瘤和2例crc以及46例非遗传性(散发性)参与者的27例腺瘤和26例crc进行FFPE组织和匹配血源DNA的全外显子组测序。对所有样品进行COSMIC v3.2 SBS突变特征评估。结果:在双等位基因MUTYH病例中,腺瘤中SBS18+SBS36的特征比例(平均值±标准差,65.6%±29.6%)与crc(76.2%±20.5%,p值=0.37)无显著差异,但与非遗传性腺瘤(7.6%±7.0%,p值=3.4 × 10-4)相比,SBS18+SBS36的特征比例显著升高。同样,在双等位基因NTHL1病例中,腺瘤中SBS30的特征比例(74.5%±9.4%)与crc相似(78.8%±2.4%),但显著高于非遗传性腺瘤(2.8%±3.6%,p值=5.1 × 10-7)。此外,在MUTYH中,与C . 1187g > a p.(Gly396Asp)致病变异和C . 533g >C p.(Gly178Ala)未知意义变异(VUS)的复合杂合子显示,在4个腺瘤和1个结直肠癌中,SBS18+SBS36水平较高,为VUS重新分类为致病变异提供了证据。结论:在腺瘤中,SBS18+SBS36和SBS30分别与双等位基因MUTYH和双等位基因NTHL1的crc中观察到的富集比例相当。因此,检测腺瘤可以提高双等位病例的识别,促进变异分类,最终为预防结直肠癌提供机会。
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Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications

Background

Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.

Methods

Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.

Results

In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, p-value=3.4 × 10–4). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, p-value=5.1 × 10–7). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.

Conclusions

SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.
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来源期刊
CiteScore
8.40
自引率
2.00%
发文量
314
审稿时长
54 days
期刊介绍: Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.
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