Amit Sud

Genome-wide association studies of cancer: current insights and future perspectives.

Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS.

Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History

Purpose Although advances in Hodgkin lymphoma (HL) treatment have led to improved disease-free survival, this has been accompanied by an increased risk of second cancers. We sought to quantify the second cancer risks and to investigate the impact of family history. Patients and Methods Using the Swedish Family-Cancer Project Database, we identified 9,522 individuals with primary HL diagnosed between 1965 and 2012. We calculated standardized incidence ratios and cumulative incidence of second cancer in HL survivors and compared the standardized incidence ratios of lung, breast, colorectal, and all second cancers in HL survivors with and without a site-specific family history of cancer. Interactions between family history of cancer and HL treatment were evaluated under additive and multiplicative models. Results Overall, the risk of a second cancer in HL survivors was increased 2.39-fold (95% CI, 2.29 to 2.53). The 30-year cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 years of age was 13.8%. We observed no significant difference in cancer risk over successive time periods. The risk of all second cancers was 1.3-fold higher for HL survivors with a first-degree relative with cancer (P < .001), with 3.3-fold, 2.1-fold, and 1.8-fold differences shown for lung, colorectal, and breast cancers, respectively. Moreover, a greater than additive interaction between family history of lung cancer and HL treatment was shown (P = .03). Conclusion HL survivorship is associated with a substantive risk of a second cancer. Notably, the risk is higher in individuals with a family history of cancer. This information should be used to inform risk-adapted therapy and to assist in screening to reduce long-term morbidity and mortality in patients with HL.

Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis.

Background While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. Methods We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. Results Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65–0.92, P = 3.9 × 10−3; ORPOA = 0.36, 95% CI: 0.15–0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93–0.98, P = 3.7 × 10−4; ORAA = 1.05, 95% CI: 1.02–1.07, P = 1.7 × 10−4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01–1.35, P = 0.041). Conclusion Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10−9) with opposing effects between CLL (P = 1.97 × 10−8) and HL (P = 3.31 × 10−3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10−12) was associated with increased CLL and HL risk (P = 4.68 × 10−12), and reduced MM risk (P = 1.12 × 10−2), and Gly70 in HLA-DQB1 (P = 3.15 × 10−10) showed opposing effects between CLL (P = 3.52 × 10−3) and HL (P = 3.41 × 10−9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Genome-wide homozygosity signature and risk of Hodgkin lymphoma.

Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3–14.1, 7p22.2, 10p11.22–23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations.

Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis

To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to Hodgkin lymphoma (HL), we conducted a systematic review and meta‐analysis of published case‐control studies. Of the variants examined more than once in candidate gene association studies, we identified 21 studies that reported on 12 polymorphic variants in 10 genes. Data were also extracted from a published genome wide association study to allow analysis of an additional 47 variants in a further 30 genes. Promising associations were seen in nine of the variants (p < 0.05). Given that the estimated false positive report probabilities (FPRPs) for all associations are high (i.e. FPRP > 0.2), these findings should be interpreted with caution. While studies of candidate polymorphisms may be an attractive means of identifying risk factors for HL, future studies should employ sample sizes adequately powered to identify variants having only modest effects on HL risk. Furthermore, because of aetiological heterogeneity within HL, stratification of genotyping according to age, tumour Epstein‐Barr virus status and histology is essential. Copyright

Influence of obesity-related risk factors in the aetiology of glioma

BackgroundObesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation.MethodsGenetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship.ResultsNo convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma–glioblastoma (GBM) or non-GBM tumours.ConclusionsThis study provides no evidence to implicate obesity-related factors as causes of glioma.

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Summary Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.