This study tested whether SNPs that are associated with adult height are also associated with risk of TGCT. We have shown tentative evidence that two of the 15 SNPs analysed, rs6060373 and rs143384, are associated with an increased risk of TGCT. Adjustment for the typed SNPs modestly attenuated the association between adult height and TGCT risk. However, the best fitting models from genome-wide association studies of adult height have only been able to account for 2–4% of its heritability, a small proportion relative to that estimated from twin and family studies (70–90%). Thus, any analysis of the genetic basis of adult height and cancer risk will be somewhat limited; a further analysis of a larger sample size may well provide more robust estimates of association, potentially confirming the findings presented herein.
Both SNPs (rs6060373 and rs143384) found to be associated with TGCT risk are located at chromosome 20q11.22. rs143384 is a 5′ UTR polymorphism of the gene growth/differentiation factor 5
), whereas rs6060373 is an intronic variant of ubiquinol-cytochrome c reductase complex chaperone
) downstream of GDF5. Many SNPs in this region, including rs6060373 and rs143384, are in linkage disequilibrium and associated with adult height.23,28,29
Due to the high degree of linkage between rs6060373 and rs143384 in our study, we could not elucidate which SNP was principally associated with TGCT risk. In a subgroup analysis of African–American samples, Sanna et al
suggested that SNPs of GDF5
are more likely to be causal variants of adult height compared with SNPs within UQCC
, thus the same may be true of TGCT if height is considered to be on the causal pathway between genetic polymorphisms and TGCT risk. SNPs within this region have also been associated with numerous skeletal abnormalities23,29
including osteoarthritis, for which there is evidence that the causal SNP is rs143383—a 5′ UTR polymorphism which influences GDF5
transcriptional activity in chondrogenic and non-chondrogenic cell lines.30,31
In our study, we found the C allele of rs143384 to be associated with an increased risk of TGCT as well as increased height. rs143384-C is in linkage disequilibrium with the C allele of rs143383, which produces higher levels of GDF5
expression. In addition, GDF5
is known to be expressed in testicular tissues including germ cells (GDS596).32
Given that GDF5
is a member of the TGF-β superfamily of genes which regulate cell growth and differentiation in both embryonic and adult tissues, the sum of evidence presents a plausible hypothesis that GDF5
polymorphisms may modify TGCT risk.24,28,32–38
Genetic polymorphisms that contribute to variation in adult height only slightly attenuated the association between adult height and TGCT risk. Elucidation and addition to our models of polymorphisms that account for a greater proportion of the estimated hereditability of this trait may provide additional resolution to the complexity of these relationships. In addition, environmental exposures are also a key influence in determining adult height; exposures such as early childhood nutrition are plausible mediators of the relationship between adult height and cancer risk.
Growth within the first 2 years of life is largely predictive of secular trends in adult height,18
underlining the fact that environmental exposures, which contribute ~20% of variability to adult height in most modern, developed countries, are mainly active within a short time-window during early post-natal development. This is relevant to TGCT not only because this malignancy is considered to have an aetiology rooted in early development, but also because TGCT incidence rates39
have closely followed secular trends in height.18,40,41
Both height and TGCT incidence increased in the early part of the 20th century and then underwent a slight decline, from ~1925–40, before subsequently increasing again until the present day. The increases in adult height, estimated to be ~10
mm per decade in Western European countries,42
are thought to be attributable to various factors associated with socio-economic status, particularly nutritional quality during pre-natal and early childhood development.18
Although trends of height, energy restriction and TGCT incidence are not entirely congruent across geographies,39–41
hypotheses of specific nutrient deficiencies remain plausible.
Strengths of this analysis include its population-based design, relatively large sample size and high response rate. In addition, the male US military population is not limited to any geographical area or subset of the population, which makes results from this study generalizable to larger US populations. The STEED Study also included only pathologically confirmed TGCT, ensuring a highly homogenous population from which precise estimates of risk may be attained. This analysis also has certain limitations. Only TGCT cases diagnosed during active duty were identified for enrolment in the case series of the study, which may have somewhat reduced the potential sample size of the study. In addition, the inability to contact men due to deployment presents a potential bias in that deployed men might be different in some way compared with non-deployed men. However, as the majority of young men in military service are healthy and fit it would seem unlikely that this would confer substantial bias, especially given that one would not expect deployed and non-deployed people to differ genetically. The analysis had limited power to assess some of the secondary aims, particularly within strata of height and histology. More important, perhaps, is the reduced power due to the weak effects of the majority of SNPs associated with height, especially given the polygenetic nature of this trait and only having typed 15 SNPs. The small number of non-White participants precluded an examination of differences in risk by ethnicity.
In conclusion, we find indicative associations between two SNPs, in LD, within the UQCC-GDF5
region on chromosome 20 and risk of TGCT. In addition, adjustment for all typed SNPs reduced the associations between adult height and TGCT by ~8.5% but this reduction was statistically weak (P
0.26). Larger studies should examine a broader scope of height-related SNPs in relation to the relationship between adult height and TGCT risk, in an attempt to assess a larger proportion of the genetic variability of adult height. If our findings are confirmed, further studies designed to further elucidate the mechanism of association would be warranted.