Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

Abstract

Objective: 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 yrs. This prompted us to reconsider the genetic analysis. Design and Methods: 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. Results: 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. Conclusion: 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 NB in the proband.

Genetic spectrum in a Canadian cohort of apparently sporadic pheochromocytomas and paragangliomas: New data on multigene panel retesting over time

“…We also found a novel VUS in the EGLN2 gene, c.547G>A p.(Val183Met) (PHEO) and in the KIF1B gene, c.4142G>C p.(Ser1381Thr) (TAPGL). A family with PHEOs carrying a KIF1B genetic alteration was found recently to carry a germline disease‐causing MAX mutation 34,35 . The novel EGLN2 missense variant c.547G>A replaces a valine for methionine at position 183.…”

Pheochromocytoma: a changing perspective and current concepts

“…7,15 Next-generation sequencing (NGS) advancements have led to its rise as a staple in genetic testing. Compared to sequential genetic testing (SGT), it allows physicians to test for specific gene panels based on each case simultaneously The role of KIF1B as a germline mutation is controversial, 25 and estimated prevalence of the mutation ranges from 0.66% to 1.1% in two cohorts. 9,26 Could be classified as VUS.…”

“… *** = case report; ** = of genetically identified tumors; * = paternal inheritance (maternal imprinting); + = low, ++ = low-intermediate; +++ = intermediate; ++++ = intermediate-high; +++++ = high; **** = there is no consensus for nuclear imaging in FH, MDH2, SLC25A11, and DLST mutations. 4 a The role of KIF1B as a germline mutation is controversial, 25 and estimated prevalence of the mutation ranges from 0.66% to 1.1% in two cohorts. 9,26 Could be classified as VUS. 3-MT, 3-methoxytyramine; PPGL, pheochromocytoma and paraganglioma; VHL, Von-Hippel Lindau; VUS, variants of undetermined significance. …”

“… a The role of KIF1B as a germline mutation is controversial, 25 and estimated prevalence of the mutation ranges from 0.66% to 1.1% in two cohorts. 9 , 26 Could be classified as VUS.…”

Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach

“…KIF1B mutations in PPGL have been described both somatic and germline [60]. However, as these variants are rare, further studies are required to clarify their role in PPGL development, as recent reports have questioned its involvement in PPGL tumorigenesis [61].…”