Azzollini Jacopo, Pesenti Chiara, Ferrari Luca, Fontana Laura, Calvello Mariarosaria, Peissel Bernard, Portera Giorgio, Tabano Silvia, Carcangiu Maria Luisa, Riva Paola, Miozzo Monica, Manoukian Siranoush
Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
PLoS One. 2017 Feb 15;12(2):e0171663. doi: 10.1371/journal.pone.0171663. eCollection 2017.
In BRCA1/2 families, early-onset breast cancer (BrCa) cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases), blood leukocytes, buccal mucosa and urine samples (2 cases) or on blood only (7 cases). In one family (n.8), real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into account in the evaluation of high-risk families.
在BRCA1/2基因家族中，非携带者亲属中也可能出现早发性乳腺癌（BrCa）病例。这些女性被视为表型模拟者，这就引发了有关索引病例选择以及阴性家族成员残余风险评估等棘手的咨询问题。很少有研究调查表型模拟者中潜在遗传易感性因素的存在情况，主要集中在与BrCa相关的单核苷酸多态性上。我们推测，与其他孟德尔疾病一样，BRCA系谱中可能也会发生由致病突变的自发纠正导致的回复性体细胞镶嵌现象。表型模拟者中一种从未被研究过的假定低水平镶嵌现象，可能是标准诊断检测未发现的致病因素。我们从15个BRCA1/2基因家族中选取了16名受BrCa影响的非携带者，并通过基质辅助激光解吸电离飞行时间质谱法研究了镶嵌现象的存在情况。分析是在可用的肿瘤样本（7例）、血液白细胞、口腔黏膜和尿液样本（2例）或仅血液样本（7例）上进行的。在一个家族（编号8）中，还进行了实时聚合酶链反应以分析表型模拟者及其健康父母。在这16名表型模拟者中，我们在预期突变频率最高的肿瘤中以及其他分析组织中均未检测到家族突变。在家族8中，所有基因分型检测均未在表型模拟者或其健康父母中检测到镶嵌现象，这支持了先证者中鉴定出的BRCA2突变是新发突变的假设。这些结果表明，体细胞镶嵌现象在BRCA1/2基因家族中不太可能是常见现象。由于我们的家族符合高风险选择标准，其他遗传因素可能是这些病例中的大多数的病因，并对BRCA1/2基因家族的风险评估产生重大影响。最后，我们发现了一个新发的BRCA2突变，这表明尽管这种情况罕见，但在评估高风险家族时应予以考虑。
