Cardot Bauters Catherine, Leteurtre Emmanuelle, Carnaille Bruno, Do Cao Christine, Espiard Stéphanie, Penven Malo, Destailleur Evelyne, Szuster Isabelle, Lovecchio Tonio, Leclerc Julie, Frénois Fredéric, Esquivel Emmanuel, Dahia Patricia L M, Ait-Yahya Emilie, Crépin Michel, Pigny Pascal
CHU Lille, Service d'Endocrinologie, Diabétologie, Métabolisme-Nutrition, Hôpital Claude Huriez, Lille, France.
Univ. Lille, Inserm, CHU Lille, UMR-S 1277-CANTHER, Cancer Heterogeneity, Plasticity & Resistance to Therapies, Lille, France.
Endocr Connect. 2020 Oct;9(10):1042-1050. doi: 10.1530/EC-20-0460.
We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband's brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis.
Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations.
A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband's brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband.
In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.
我们之前描述过一个家族，其中嗜铬细胞瘤（PCC）的易感性在三代人中与一种种系杂合的KIF1B核苷酸变体（c.4442G>A，p.Ser1481Asn）共分离。在临床随访期间，一名先证者的哥哥，KIF1B核苷酸变体检测为阴性，在31岁时患了双侧PCC。这促使我们重新考虑基因分析。
通过使用多基因panel加MLPA的二代测序（NGS）或全外显子组测序（WES）分析种系DNA。通过SnapShot、桑格测序或NGS分析肿瘤来源的DNA，以鉴定杂合性缺失（LOH）或其他体细胞突变。
在先证者的哥哥中鉴定出一个MAX基因中意义不明的种系杂合变体（c.145T>C，p.Ser49Pro）。在他的PCC中发生了野生型MAX等位基因的缺失，从而证明该变体是导致该患者双侧PCC的原因。先证者及其患病的祖父也携带MAX变体，但在体细胞水平未发现第二次打击。通过对先证者种系的WES，在36个易患家族性PCC/PGL或家族性癌症的基因中未检测到其他致病突变。在其他基因TFAP2E和TMEM214中检测到的种系变体可能与先证者的多种肿瘤有关。
在这个家族中，PCC的遗传性与MAX种系变体有关，而与KIF1B种系变体无关，不过KIF1B种系变体可能促成了先证者神经母细胞瘤（NB）的发生。
