■来自MUTYH或NTHL1中具有双等位基因种系可能致病性/致病性变异体的人的结直肠癌(CRC)表现出特定的单碱基取代(SBS)突变特征,即组合SBS18和SBS36(SBS18+SBS36),和SBS30,分别。目的是确定来自双等位基因病例的腺瘤是否在诊断水平上证明了这些突变特征。
■对来自13个双等位基因MUTYH病例的9个腺瘤和15个CRC进行了FFPE组织和匹配的血液来源DNA的全外显子组测序,来自5个双等位基因NTHL1病例的7个腺瘤和2个CRC,以及来自46个非遗传性(散发性)参与者的27个腺瘤和26个CRC。评估所有样品的COSMICv3.2SBS突变特征。
■在双等位基因MUTYH案例中,腺瘤中的SBS18+SBS36签名比例(平均值±标准偏差,65.6%±29.6%)与CRC中观察到的那些没有显着差异(76.2%±20.5%,p值=0.37),但与非遗传性腺瘤相比明显更高(7.6%±7.0%,p值=3.4x10-4)。同样,在双等位基因NTHL1病例中,腺瘤中的SBS30特征比例(74.5%±9.4%)与CRC(78.8%±2.4%)相似,但与非遗传性腺瘤(2.8%±3.6%,p值=5.1x10-7)。此外,一种复合杂合子,具有c.1187G>Ap。(Gly396Asp)致病性变异和c.533G>Cp。(Gly178Ala)在MUTYH中具有未知意义(VUS)的变异,在四个腺瘤和一个CRC中显示出高水平的SBS18SBS36,为VUS重新分类为致病性提供证据。
■SBS18+SBS36和SBS30在双等位基因MUTYH和双等位基因NTHL1病例的CRCs中观察到相当比例的腺瘤中富集,分别。因此,检测腺瘤可以改善双等位基因病例的识别,并促进变异分类,最终为预防儿童权利公约提供机会。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions 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.