To the Editor: First, we thank Trevisson et al.1 for their valuable contribution to this subject and their comments on our brief report. In our study, we reported a familiar schwannomatosis without mutations of SMARCB1/INI1/hSNF5 and LZTR, the two known causative genes for schwannomatosis. Using genome and exome sequencing, we found a heterozygous loss-of-function mutation of the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 (COQ6) gene in patients affected by disease.2 CoQ10 is an electron carrier in the mitochondrial respiratory chain, as well as a lipid-soluble antioxidant implicated in protecting cells from damage by reactive oxygen species. Its biosynthesis is still not well characterized in human cells. Mutations in CoQ10 biosynthesis genes, including COQ4 and COQ6, cause primary CoQ10 deficiency. The manifestations of primary CoQ10 deficiency are very heterogeneous, and CoQ10 deficiency has been involved in many common disorders with increased oxidative stress, such as neurodegenerative diseases, cancer, cardiovascular diseases, diabetes mellitus, aging, and Alzheimer disease. It is well known that chronic increases in oxidative stress may trigger transformation and contribute to cancer progression by amplifying genomic instability. We proposed that the halpoinsufficiency of COQ6 monooxygenase due to a loss-of-function mutation may lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells, thereby predisposing to schwannomatosis.
A critical issue of the hypothesis is whether heterozygous loss-of-function COQ6 causes haploinsufficiency. A previous study of yeast found that haploinsufficiency of COQ6 resulted in a mild reduction of fitness in a medium containing glucose.3 Moreover, we assumed that the haploinsufficiency of the COQ6 gene and CoQ10 deficiency may be conditional, dynamic, and tissue/cell specific. For example, one study found that cellular and tissue concentrations of CoQ10 decrease with age, and cellular concentrations below a critical threshold are incompatible with life. Furthermore, carcinogenesis is determined not only by genetic alterations but also gene–environment interaction, as well as metabolism, and not all transgenic mice with the exactly same genetic background and alterations may develop cancers. In addition, germ-line abnormalities associated with cancer may be detected in every cell in the body or only in the tumor cells. Interestingly, despite the presence of a constitutional genetic abnormality that might affect growth regulatory pathways in all cells, people are generally predisposed to only certain tumor types. The average age at disease onset was ~40 years for this familial schwannomatosis, indicating a chronic disease progression. In this particular family, we considered that the loss-of-function COQ6 allele may lead to a chronic or conditional haploinsufficiency of COQ6 in a cell/tissue-specific manner.
So far, the roles of mutations of CoQ10 biosynthetic genes in cancers are completely unknown. The association is only now coming of age, for example, the most recent cancer genomic studies identify COQ2 gene mutations in human melanoma, colon and rectal cancers, ovarian carcinoma, and glioblastoma multiforme. In addition, more than 48 missense mutations of the COQ6 gene have been identified in various human cancers (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic). Furthermore, abnormally low plasma concentrations of CoQ10 have been found in a number of cancer types, including cervical cancer, breast cancer, and melanoma.4 Although intensive research is needed to further explore the underlying mechanisms, increasing data have strongly indicated an undetermined implication of CoQ10 biosynthesis gene mutations in carcinogenesis.
Indeed, the exact oncogenic mechanism of the loss-of-function COQ6 gene in disease remains a challenging question to be elucidated. Cancer is a complex multigenic disease associated with diverse genetic and epigenetic alterations. In addition to the mutation of the COQ6 gene, 11 shared heterozygous variants, including MYPN, COQ6, CKMT1A, CYP11A1, DUOX1, and TRIOBP, were identified in members of the family affected by disease. Potential pathogenetic roles of these mutations should also be carefully studied and excluded. We accept these as limitations of our study. In addition, we hope this brief report serves the useful purpose of stimulating such additional genetic studies in the future. We believe that future studies will bring further insight into the oncogenic roles of alterations of CoQ10 biosynthesis genes and novel mechanisms of schwannomatosis without known causative gene alterations.
The authors declare no conflict of interest.