Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10-15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools (i.e., the single-nucleotide polymorphism, SNP) to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care.

Fcγ-receptors (FcγR) provide a critical link between humoral and cellular immunity. The genes of the low-affinity receptors for IgG and their isoforms, namely, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, and SH-FcγRIIIb, are located in close proximity on chromosome 1q22. Variant alleles may differ in biologic activity and a number of studies have reported the frequencies of variant FcγR alleles in both disease and control populations. No large study has evaluated the possibility of a nonrandom distribution of variant genotypes. We analyzed 395 normal individuals (172 African Americans [AA] and 223 Caucasians [CA]) at the following loci: FcγRIIa, FcγRIIIa, and FcγRIIIb, including the SH-FcγRIIIb. The genotypic distributions of FcγRIIa, FcγRIIIa, and FcγRIIIb conform to the Hardy-Weinberg law in each group. There was no strong evidence that combinations of 2-locus genotypes of the 3 loci deviated from random distributions in these healthy control populations. The distribution of SH-FcγRIIIb is underrepresented in CA compared with AA (P < .0001) controls. A previously reported variant FcγRIIb was not detected in 70 normal individuals, indicating that this allele, if it exists, is very rare (<1%). In conclusion, we present data that should serve as the foundation for the interpretation of association studies involving multiple variant alleles of the low-affinity FcγR.

Blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a down-regulator of T-cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated 7 common single nucleotide polymorphisms, SNPs, (rs733618, rs4553808, rs11571317, rs5742909, rs231775, rs3087243, and rs7565213) in 152 white melanoma patients who received CTLA-4 blockade. Three SNPs were associated with response to therapy: proximal promoter SNPs, rs4553808 [P=0.002; odds ratio (OR) 3.39; 95% confidence interval (CI), 1.62-7.10] and rs11571327 (P=0.02; OR 2.89; 95% CI, 1.23-6.83) and the nonsynonymous SNP rs231775 (Thr17Ala, P=0.009; OR 0.39; 95% CI, 0.18-0.82). A haplotype analysis including the 7 SNPs suggested that the common haplotype, TACCGGG could be associated with no response (P=0.02) whereas the haplotype TGCCAGG (P=0.06; OR 4.13; 95% CI, 1.17-14.5) could be associated with response to the treatment. No significant association was observed for occurrence of severe autoimmune reactions (grade III/IV) either by single SNP or haplotype analyses. Our results suggest that genetic variation in CTLA4 could influence response to CTLA-4 blockade therapy in metastatic melanoma patients, but further studies are necessary to confirm the observed associations.

Kaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1α, IL-1β, tumor necrosis factor (TNF) α, TNF-β, and IL-6 and in the IL-1 receptor antagonist (IL1RN). We also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Δ32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P = .0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P = .0046), whereas allele C homozygotes were underrepresented (P = .0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show thatIL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.

The genomic revolution has generated an extraordinary resource, the catalog of variation within the human genome, for investigating biological, evolutionary and medical questions. Together with new, more efficient platforms for high‐throughput genotyping, it is possible to begin to dissect genetic contributions to complex trait diseases, specifically examining common variants, such as the single nucleotide polymorphism (SNP). At the same time, these tools will make it possible to identify determinants of disease with the expectation of eventually, tailoring therapies based upon specific profiles. However, a number of methodological, practical and ethical issues must be addressed before the analysis of genetic variation becomes a standard of clinical medicine. The currents of variation in human biology are reviewed here, with a specific emphasis on future challenges and directions.