在 和 基因中携带致病性双等位基因变异的个体的腺瘤表现出与结直肠癌相似的碱基切除修复肿瘤突变特征谱，拓展了潜在的诊断和变异分类应用。
Adenomas from individuals with pathogenic biallelic variants in the and genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications.
作者信息
Walker Romy, Joo Jihoon E, Mahmood Khalid, Clendenning Mark, Como Julia, Preston Susan G, Joseland Sharelle, Pope Bernard J, Medeiros Ana B D, Murillo Brenely V, Pachter Nicholas, Sweet Kevin, Spigelman Allan D, Groves Alexandra, Gleeson Margaret, Bernatowicz Krzysztof, Poplawski Nicola, Andrews Lesley, Healey Emma, Gallinger Steven, Grant Robert C, Win Aung K, Hopper John L, Jenkins Mark A, Torrezan Giovana T, Rosty Christophe, Macrae Finlay A, Winship Ingrid M, Buchanan Daniel D, Georgeson Peter
机构信息
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
出版信息
medRxiv. 2024 Aug 9:2024.08.08.24311713. doi: 10.1101/2024.08.08.24311713.
BACKGROUND
Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in or 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 cases, on 7 adenomas and 2 CRCs from 5 biallelic 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 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%, =0.37), but were significantly higher compared with non-hereditary adenomas (7.6%±7.0%, =3.4×10). Similarly, in biallelic 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%, =5.1×10). 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 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 observed in CRCs from biallelic and biallelic cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.
背景
携带双等位基因种系可能致病/致病变体的人的结直肠癌（CRC）分别表现出特定的单碱基替换（SBS）突变特征，即组合SBS18和SBS36（SBS18 + SBS36）以及SBS30。目的是确定双等位基因病例的腺瘤在诊断水平上是否表现出这些突变特征。
方法
对来自13例双等位基因 病例的9例腺瘤和15例CRC、来自5例双等位基因 病例的7例腺瘤和2例CRC以及来自46例非遗传性（散发性）参与者的27例腺瘤和26例CRC进行福尔马林固定石蜡包埋（FFPE）组织和匹配的血液来源DNA的全外显子测序。所有样本均评估COSMIC v3.2 SBS突变特征。
结果
在双等位基因 病例中，腺瘤中SBS18 + SBS36特征比例（平均值±标准差，65.6%±29.6%）与CRC中观察到的比例（76.2%±20.5%，P = 0.37）无显著差异，但与非遗传性腺瘤（7.6%±7.0%，P = 3.4×10）相比显著更高。同样，在双等位基因 病例中，腺瘤中SBS30特征比例（74.5%±9.4%）与CRC中相似（78.8%±2.4%），但与非遗传性腺瘤（2.8%±3.6%，P = 5.1×10）相比显著更高。此外，一名携带c.1187G>A p.(Gly396Asp)致病变体和c.533G>C p.(Gly178Ala)意义未明变体（VUS）的复合杂合子在 中的4例腺瘤和1例CRC中表现出高水平的SBS18 + SBS36，为将该VUS重新分类为致病提供了证据。
结论
SBS18 + SBS36和SBS30在腺瘤中富集，其比例分别与双等位基因 和双等位基因 病例的CRC中观察到的比例相当。因此，检测腺瘤可能改善双等位基因病例的识别并促进变体分类，最终为CRC预防创造机会。
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