Su Elena, Christinat Yann, McKee Thomas, Azzarello-Burri Silvia, Jochum Wolfram, Fischer Stefanie, Rothermundt Christian
Department of Gynecology, Cantonal Hospital St. Gallen, Rorschacher Strasse 95, St. Gallen, 9007, Switzerland.
Department of Clinical Pathology, Geneva University Hospitals, Rue Gabrielle-Perret- Gentil 4, Geneva, 1206, Switzerland.
Hered Cancer Clin Pract. 2024 Dec 19;22(1):27. doi: 10.1186/s13053-024-00302-7.
BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored.
We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin.
Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history.
已知BRCA2种系突变会使携带者易患多种癌症类型，包括乳腺癌、卵巢癌、胰腺癌和前列腺癌。也有报道称其与黑色素瘤有关联。然而，与BRCA2突变相关的完整肿瘤谱，尤其是在伴有其他并发致病突变的患者中，尚未得到充分研究。
我们报告一名70岁女性患者，携带致病性BRCA2 c.5946del变异。在15年的时间里，她先后患了两种独立的乳腺癌、高分化脂肪肉瘤、透明细胞肾细胞癌和骨髓增殖性肿瘤。这种不寻常的肿瘤谱以及这些肿瘤的交错发生需要进行多轮基因检测，并导致BRCA2相关肿瘤易感性的诊断延迟。除了BRCA2突变外，扩展的种系检测还发现了一个APC c.3920T>A变异以及BRIP1和ATR基因中意义不明的变异。对肿瘤的分子分析显示出不同的特征，在同源重组缺陷（HRD）状态和拷贝数变异方面存在差异，表明它们并非起源于共同的肿瘤。
我们的病例研究表明，致病性BRCA2 c.5946del种系变异可能与不寻常的肿瘤谱相关，这可能导致遗传性肿瘤易感性的诊断延迟。因此，鼓励使用大型多基因检测板或全基因组测序进行前期基因检测，尤其是在有明显家族史的病例中。
