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Abstract：
Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation.
We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history.
Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH).
Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.
We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history.
Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH).
Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.
摘要：
背景：尽管下一代测序（NGS）的使用越来越多，关于种系致病变异(PV)增加的数据仍然很少，尤其是关于不规范的。我们旨在验证不同癌症易感性基因（CPG）对转诊进行遗传评估的患者的结直肠癌（CRC）的影响。
方法：我们注册了NGS，由IlluminaTruSight癌症小组组成，包括94个CPG，190名连续受试者因微卫星不稳定性(MSI)CRC，息肉病,和/或家族史。
结果：总体而言，51例(26.8%)受试者携带64例PVs；PVs共存于4例(7.8%)携带者中。错配修复（MMR）基因中的PV占变体负担的三分之一（31.3％）。四名Lynch综合征患者（20％）携带额外的PV（HOXB13，CHEK2，BRCA1，NF1加BRIP1）；此类多个PV仅发生在具有失配综合征基因的PV的受试者中（4/20对0/31；P=0.02）。22名（22.7％）MSI癌症患者中有5名，但野生型MMR基因在非常规基因中携带PVs（FANCL，范卡,ATM,PTCH1,BAP1)。在10/63例（15.9%）微卫星稳定CRC患者中，6个有MUTYHPV(2个是纯合的)，4个有不规范的PV(BRCA2，BRIP1，MC1R，ATM）。在息肉病中，我们在13例(25.5%)中检测到PVs：在APC中检测到5例(9.8%)，6（11.8%）在MUTYH中具有双等位基因PV，和2个(3.9%)在非规范基因(FANCM，XPC）。在仅测试家族史的受试者中，我们检测到两个带有PV的运营商(18.2%)(ATM，MUTYH).
结论：非规范变体可能占PV的三分之一，强调迫切需要就与患者表型无关的癌症易感基因中偶然发现的临床建议达成共识。
方法：我们注册了NGS，由IlluminaTruSight癌症小组组成，包括94个CPG，190名连续受试者因微卫星不稳定性(MSI)CRC，息肉病,和/或家族史。
结果：总体而言，51例(26.8%)受试者携带64例PVs；PVs共存于4例(7.8%)携带者中。错配修复（MMR）基因中的PV占变体负担的三分之一（31.3％）。四名Lynch综合征患者（20％）携带额外的PV（HOXB13，CHEK2，BRCA1，NF1加BRIP1）；此类多个PV仅发生在具有失配综合征基因的PV的受试者中（4/20对0/31；P=0.02）。22名（22.7％）MSI癌症患者中有5名，但野生型MMR基因在非常规基因中携带PVs（FANCL，范卡,ATM,PTCH1,BAP1)。在10/63例（15.9%）微卫星稳定CRC患者中，6个有MUTYHPV(2个是纯合的)，4个有不规范的PV(BRCA2，BRIP1，MC1R，ATM）。在息肉病中，我们在13例(25.5%)中检测到PVs：在APC中检测到5例(9.8%)，6（11.8%）在MUTYH中具有双等位基因PV，和2个(3.9%)在非规范基因(FANCM，XPC）。在仅测试家族史的受试者中，我们检测到两个带有PV的运营商(18.2%)(ATM，MUTYH).
结论：非规范变体可能占PV的三分之一，强调迫切需要就与患者表型无关的癌症易感基因中偶然发现的临床建议达成共识。
