Three different mechanisms may underlie the totality of familial TGCT. First, familial TGCT may be a classical Mendelian disorder that is caused by germline mutations in rare, high penetrant, yet-to-be-discovered genes. A second subset of familial TGCT may be genetically driven by a polygenic disorder associated with several common, low penetrant susceptibility alleles. A third subset may be due to primarily shared environmental exposures in members of individual families. Of course, genetic and environmental factors may modulate the risk in each basic type. However, the clear replication signals of SNPs implicated in familial disease strongly suggests that familial, bilateral, and sporadic tumours are polygenic diseases driven by the same spectrum of genetic risk factors. Previous linkage studies that did not detect loci with consistently high logarithm of odds (LOD) scores,21,22
the three recent GWAS,11–13
and our findings are consistent with this model.
Our study provides the first replication of the recently identified TGCT risk loci in DMRT1
, and the second replication of previously identified predisposition alleles in BAK1
. Moreover, we provided evidence for a new and independent signal in TERT
that requires further verification. Although the reported GWAS focused on non-familial TGCT, they also included subsets of patients with familial disease or bilateral disease.11–13
All three GWAS demonstrated similar ORs in familial TGCT cases compared with those TGCT cases without a family history.11–13
Therefore, our results from an independent set of previously unstudied familial cases strengthen the notion that familial and sporadic TGCT are polygenic diseases associated with the same genetic factors.
We compared the ORs obtained from our study with those reported in the previous GWAS, and found that they are quite similar; the reported ORs for rs4635969 in TERT
were 1.65 and 1.5413
and ours is 1.59; for KITLG
, the reported ORs were 2.29 and 2.59 for rs99503012
and we obtained an OR of 2.33 for rs2046971, which is in high LD with rs995030; for DMRT1
, we obtained slightly higher ORs compared to the previous findings; for rs210138 in BAK1
, the reported OR was 1.512
while ours is 1.8; for rs755383 in DMRT1
, we have an OR of 1.67, which is larger than 1.57 and 1.37 which were previously reported.13
Also, previous studies reported that <1% of sporadic cases were homozygous for the non-risk minor allele in rs4474514 in KITLG
and we found that such a pattern was observed in familial cases in our data; one of 97 familial cases (1%) was homozygous for non-risk minor allele in rs2046971 in KITLG
and none of 22 sporadic cases were homozygous in this SNP.
Our analytic method accounted for correlations between relatives, and thereby increased the power to detect associations because it allowed us to include all affected members from each individual family. This method may be useful to explore large scale genetic association analyses in other complex disorders with strong heritability but unclear linkage signals. Due to sample size limitations of the present study, our approach was better suited for testing prior hypotheses rather than agnostically detecting novel associations. The control group is a convenience sample not closely matched in age, but it is unlikely that this matters given the comparatively early onset of this disease. Another limitation was that bilateral and familial cases were not separated in this analysis. Notably, the three GWAS did not observe differences between these subgroups, suggesting that they do not represent biologically distinct entities.
In conclusion, this is the first large scale genotyping effort focusing exclusively on subjects with familial or bilateral TGCT. Using a statistical approach that accounted for familial relationships, we confirmed results from recent GWAS and identified familial/bilateral TGCT risk alleles in KITLG, BAK1, TERT, and DMRT1. We provided evidence for a new and independent signal in TERT that requires further verification. Together with the results from previous GWAS, our data suggest that familial TGCT and bilateral and sporadic TGCT are polygenetic diseases caused by the same spectrum of genetic risk factors.