Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, University Campus, bld. 17b, 54124, Thessaloníki, Greece.
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloníki, Greece.
Breast Cancer. 2021 Nov;28(6):1367-1382. doi: 10.1007/s12282-021-01276-3. Epub 2021 Jul 24.
The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points.
Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples.
High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable.
This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.
携带致病性种系 BRCA1/2（gBRCA1/2）变异的非恶性组织的基因组状态可能揭示针对个体化预防的信息。我们对来自希腊裔 gBRCA1/2 携带者的真实队列进行了时空组织基因型比较，这些携带者在不同时间点接受了多次降低风险/预防手术。
对多达 37.5 年的 53 名癌症家族女性（中位年龄 36 岁）进行观察；其中 43 名是癌症携带者，10 名是健康携带者。对 187 个石蜡组织（平均每个携带者 3.5 个）进行组织学检查和基因分型，包括 46 个癌（40 个乳腺）和 141 个非恶性乳腺和妇科样本。
高等位基因不平衡（AI）和体细胞致病性 TP53 变异仅存在于癌症携带者中（p 值均<0.0001）。高 AI 与 gBRCA1/2 插入缺失（p<0.0001）和 gBRCA2 改变（p=0.0109）相关。体细胞（致病性）变异在非恶性组织和匹配的癌之间很少共享。仅在癌症携带者的组织中发现 gBRCA1 变体杂合性缺失（13/43，30.2%）。这些涉及经典 LOH（43 名携带者中的 9 个，20.9%）和种系变异的代表性不足（5 个样本，4 个非恶性，均在乳腺中）。在一个病例中，这两种异常在匹配样本中同时存在。随着时间的推移，种系变异的杂合性在非恶性组织中占主导地位；携带者内的基因组改变恶化（21.1%）、减轻（26.3%）或保持稳定。
这项真实案例研究支持需要结合多基因评分来解决预防性手术中的组织基因型问题，以实现个体化预防。为此，仅了解 gBRCA1/2 变异的传统分类致病性潜力可能还不够。
