Modulate Cancer Susceptibility Research Articles

Integrating bulk and single-cell RNA sequencing data reveals the relationship between intratumor microbiome signature and host metabolic heterogeneity in breast cancer.

Nowadays, it has been recognized that gut microbiome can indirectly modulate cancer susceptibility or progression. However, whether intratumor microbes are parasitic, symbiotic, or merely bystanders in breast cancer is not fully understood. Microbial metabolite plays a pivotal role in the interaction of host and microbe via regulating mitochondrial and other metabolic pathways. And the relationship between tumor-resident microbiota and cancer metabolism remains an open question. 1085 breast cancer patients with normalized intratumor microbial abundance data and 32 single-cell RNA sequencing samples were retrieved from public datasets. We used the gene set variation analysis to evaluate the various metabolic activities of breast cancer samples. Furthermore, we applied Scissor method to identify microbe-associated cell subpopulations from single-cell data. Then, we conducted comprehensive bioinformatic analyses to explore the association between host and microbe in breast cancer. Here, we found that the metabolic status of breast cancer cells was highly plastic, and some microbial genera were significantly correlated with cancer metabolic activity. We identified two distinct clusters based on microbial abundance and tumor metabolism data. And dysregulation of the metabolic pathway was observed among different cell types. Metabolism-related microbial scores were calculated to predict overall survival in patients with breast cancer. Furthermore, the microbial abundance of the specific genus was associated with gene mutation due to possible microbe-mediated mutagenesis. The infiltrating immune cell compositions, including regulatory T cells and activated NK cells, were significantly associated with the metabolism-related intratumor microbes, as indicated in the Mantel test analysis. Moreover, the mammary metabolism-related microbes were related to T cell exclusion and response to immunotherapy. Overall, the exploratory study shed light on the potential role of the metabolism-related microbiome in breast cancer patients. And the novel treatment will be realized by further investigating the metabolic disturbance in host and intratumor microbial cells.

Obesity, Fat Distribution and Risk of Cancer in Women and Men: A Mendelian Randomisation Study.

Obesity and upper-body fat distribution are independent, cardiometabolic risk factors but whether they also display comparable associations with cancer risk is unknown. We investigated the causal relationships between body mass index (BMI) and BMI-adjusted waist-to-hip ratio (WHRadjBMI) and cancer risk and searched for potential drivers linking these traits to carcinogenesis using two-sample and multivariable Mendelian randomisation. In women, genetically instrumented higher BMI was associated with lower breast (OR = 0.87, 95% CI 0.81-0.93) and higher endometrial (OR = 1.75, 95% CI 1.55-1.96) cancer risk whilst WHRadjBMI was associated with higher colon cancer risk (OR = 1.22, 95% CI 1.07-1.42). In men, elevated BMI was associated with lower prostate cancer risk (OR = 0.91, 95% CI 0.85-0.98). Mechanistically, testosterone and insulin mediated 21% and 35%, respectively of the total, genetically determined association of BMI with endometrial cancer risk whilst HDL cholesterol and IGF-1 mediated 40% and 22%, respectively of the association between BMI and breast cancer risk. In men, testosterone mediated 21% of the association between BMI and prostate cancer risk. Colon cancer aside, the total amount of body fat might be more important than its location in modulating cancer susceptibility due to differential effects of obesity and fat distribution on adiposity-associated cancer drivers.

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil.

Admixed populations have not been examined in detail in cancer genetic studies. Here, we inferred the local ancestry of cancer-associated single nucleotide polymorphisms (SNPs) and haplotypes of a highly admixed Brazilian population. SNP array was used to genotype 73 unrelated individuals aged 80-102 years. Local ancestry inference was performed by merging genotyped regions with phase three data from the 1000 Genomes Project Consortium using RFmix. The average ancestry tract length was 9.12-81.71 megabases. Strong linkage disequilibrium was detected in 48 haplotypes containing 35 SNPs in 10 cancer driver genes. All together, 19 risk and eight protective alleles were identified in 23 out of 48 haplotypes. Homozygous individuals were mainly of European ancestry, whereas heterozygotes had at least one Native American and one African ancestry tract. Native-American ancestry for homozygous individuals with risk alleles for HNF1B, CDH1, and BRCA1 was inferred for the first time. Results indicated that analysis of SNP polymorphism in the present admixed population has a high potential to identify new ancestry-associated alleles and haplotypes that modify cancer susceptibility differentially in distinct human populations. Future case-control studies with populations with a complex history of admixture could help elucidate ancestry-associated biological differences in cancer incidence and therapeutic outcomes.

Abstract 2907: A metaproteomic approach to study the host-microbiota interaction in cancer tissue

Abstract Background: The microbiota has the ability to modulate cancer susceptibility through a systemic interaction with the host that occurs also at tissue level. Unraveling the functional meaning of the microbiota in the tumoral microenvironment is crucial to understand its causal role. Metagenomic approaches identify the microbial composition but not its functional role. In this study, we exploited a metaproteomic approach to investigate the presence of microbiota-derived proteins on breast cancer (BC) tumoral and healthy tissues using formalin-fixed paraffin-embedded (FFPE) samples, and to assess the interaction with human proteome Material and methods: Three tumoral regions (peripheral tumor, tumor core, in situ carcinoma) and 2 healthy areas (intra-tumoral fibrosis, healthy tissue) were selected on 5 FFPE BC samples, 3 triple negative and 2 luminal, chosen based on the year of inclusion in FFPE (2017-2018). The proteomic analysis was performed on 10 µm tissue slides, by nanoLC-MS/MS analysis and data analysis by Perseus and Maxquant. Results: The proteomic analysis revealed the presence of 13 microbial proteins. Seven proteins are involved in energy production and metabolism, 4 are chaperonins. Most of the proteins were found in the intra tumoral fibrosis. Two Chaperone proteins DnaK (Thermosipho melanesiensis etc. and Rhodothermus marinus) and an S-adenosylmethionine synthase (MAT2A) (Homo sapiens; Helicobacter hepaticus etc.) were overexpressed in tumor tissue compared to the healthy. 1073 human proteins were identified and 78 were overexpressed. KEGG analysis revealed that the proteins overexpressed in healthy tissues are involved in the maintenance of cell and tissue structure and function, protein digestion and absorption, mediator of innate immunity and nonspecific defense mechanism against pathogens. The proteins overexpressed in tumor tissues belong to protein processing, antigen processing and presentation, carbon metabolism and phagosome or E.coli infection pathways Discussion: A proteomic approach on tumor tissue can give functional information about the host-microbiota interactions. Our preliminary data shows an overexpression in tumor samples, in particular in intra tumoral fibrosis, of DnaKs and MAT2A. The first are bacterial chaperone proteins able to interfere with important pathways related to DNA damage control/repair, cell-cycle/apoptosis and is a cancer promoter. The second protein is an enzyme essential for methylation that can confer growth and survival advantage to cancerous cells, enhancing tumor migration. Most of the bacterial proteins identified are involved in energy production or chaperonins. Taken together the bacterial and human proteome results, it seems that bacteria supply the tumor cells with important proteins that promote cancer growth and which fit perfectly into the pathways most represented in the tumor. More studies are needed to confirm the hypothesis. Citation Format: Francesca Pirini, Tania Rossi, Soulaimane Aboulouard, Giovanni Martinelli, Sara Bravaccini, Michel Salzet. A metaproteomic approach to study the host-microbiota interaction in cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2907.

HMGA2 Gene rs8756 A>C Polymorphism Reduces Neuroblastoma Risk in Chinese Children: A Four-Center Case-Control Study.

BackgroundNeuroblastoma, mainly affecting children, is a lethal malignancy arising from the developing sympathetic nervous system. The genetic etiology of neuroblastoma remains mostly obscure. High mobility group AT-hook 2 (HMGA2), an oncogenic gene, is up-regulated in many tumors. Single nucleotide polymorphisms (SNPs) often modify cancer susceptibility. However, no studies are investigating the association between HMGA2 SNPs and neuroblastoma susceptibility.MethodsWe conducted a four-center case-control study to evaluate the association between three HMGA2 polymorphisms (rs6581658 A>G, rs8756 A>C and rs968697 T>C) and neuroblastoma susceptibility in a Chinese population with 505 cases and 1070 controls. Logistic regression was performed to evaluate the strength of the association.ResultsWe found that the rs8756 AC/CC genotypes were associated with a reduced neuroblastoma risk when compared to rs8756 AA genotype [Adjusted odds ratio (OR)=0.74, 95% confidence interval (CI)=0.56–0.99, P=0.039]. Carriers with 3 protective genotypes have lower neuroblastoma susceptibility than those without or with 0–2 protective genotypes. The stratified analysis revealed that the protective effects of rs8756 AC/CC genotypes were more predominant among children of age > 18 months, males, and subgroups with the tumor in the mediastinum. Furthermore, haplotype analysis uncovered that haplotype ACC significantly reduced neuroblastoma risk.ConclusionOur study indicated HMGA2 rs8756 A>C polymorphism is significantly associated with decreased neuroblastoma risk.

Association of miR-34b/c rs4938723 and TP53 Arg72Pro Polymorphisms with Neuroblastoma Susceptibility: Evidence from Seven Centers

Neuroblastoma is a pediatric malignancy arising from the developing peripheral nervous system. p53 and downstream effector miR-34b/c have critical tumor suppressing functions. TP53 Arg72Pro (rs1042522 C > G) and miR-34b/c rs4938723 (T > C) polymorphisms have been known to modify cancer susceptibility. This study was performed to validate the association of these two polymorphisms and neuroblastoma risk with 819 cases and 1780 controls. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to assess the strength of the associations. False positive report possibility analysis was adopted to dissect out real significant associations from chance findings. We found that both TP53 Arg72Pro (CG/GG vs. CC: adjusted OR = 0.82, 95% CI = 0.69-0.98) and miR-34b/c rs4938723 (TC/CC vs. TT: adjusted OR = 0.64, 95% CI = 0.54-0.75) were associated with decreased neuroblastoma susceptibility. Stratify analyses further confirmed the protective effect among some subgroups. Moreover, subjects with variant alleles of both polymorphisms were associated with more significantly decreased neuroblastoma risk (CG/TC vs. CC/TT: adjusted OR = 0.38, 95% CI = 0.28-0.50; GG/TC vs. CC/TT: adjusted OR = 0.43, 95% CI = 0.30-0.63) than those carrying variant allele of either one polymorphism (CC/TC vs. CC/TT: adjusted OR = 0.51, 95% CI = 0.37-0.69; CG/TT vs. CC/TT: adjusted OR = 0.71, 95% CI = 0.55-0.92), suggesting cumulative effects of the polymorphisms. False positive report possibility analysis further verified that our findings are noteworthy. Overall, we confirmed that miR-34b/c rs4938723 and TP53 Arg72Pro conferred decreased neuroblastoma risk and two polymorphisms exerted stronger protective effects against neuroblastoma than either one alone.

HIF1A genetic variability and late adverse events of radiotherapy in breast cancer.

e12069 Background: Hypoxia-inducible factors (HIFs) are transcription factors that play an important part in the regulation of various cell processes involved in carcinogenesis such as cell proliferation, apoptosis, angiogenesis, and metastasis. Additionally, hypoxia could influence response to radiotherapy and radiation was shown to stabilize HIF-1α and affect release of cytokines. Previous studies have already shown that HIF1A genetic variability may modify cancer susceptibility, but data on its influence on treatment response are scarce. As nicotine induces HIF-1α expression, smoking could also modify treatment response. Our aim was to evaluate the association of common functional HIF1A rs11549465 polymorphism and smoking with late adverse events of radiotherapy in breast cancer patients. Methods: Our pilot retrospective study included 92 HER2-positive early breast cancer patients treated with adjuvant radiotherapy between 2005 and 2011. We isolated DNA from buccal swabs and genotyped all patients for HIF1A rs11549465 using competitive allele-specific PCR. Association of polymorphisms with adverse events and interaction with smoking was evaluated using logistic regression. Results: Median follow-up after radiotherapy was 4.2 (2.6-5.5) years. Overall, 30 (32.6%) patients reported late adverse events according to LENT-SOMA criteria, and 11 (12.0%) experienced skin toxicity according to CTCAE v.4.0 (Common Terminology Criteria for Adverse Events). Only 15 (16.3%) of patients were smokers. Minor allele frequency of HIF1A rs11549465 was 0.07. The studied polymorphism was not associated with late adverse events (OR = 0.75, 95% CI = 0.18-3.06, P = 0.688) or late skin toxicity (OR = 0.71, 95% CI = 0.08-6.15, P = 0.756) in our cohort of patients. We also observed no interaction between smoking, HIF1A genetic variability and late adverse events of radiotherapy. Conclusions: HIF1A rs11549465 was not associated with late adverse events of radiotherapy even if smoking was taken into account in our cohort of breast cancer patients.

CASP9 c.-1339A>G and CASP3 c.-1191A>G polymorphisms alter susceptibility and clinical aspects of head and neck squamous cell carcinoma.

Single nucleotide polymorphisms (SNPs) in genes that act in intrinsic apoptosis pathway may modulate cancer susceptibility. This study investigated the roles of CASP9 c.-1339A>G (rs4645978) and CASP3 c.-1191A>G (rs12108497) SNPs on risk and behavior of head and neck (HN) squamous cell carcinoma (SCC). DNA of 350 patients with HNSCC and 350 controls was analyzed by polymerase chain reaction method for genotyping. CASP3 c.-1191AG or GG genotype was more common in patients with HNSCC and oral cavity or oropharynx SCC than in controls; carriers of this genotype were under 2.15 and 2.81-fold increased risks of the respective tumors. CASP9 c.-1339AG or GG plus CASP3 c.-1191AG or GG genotypes were associated with oral cavity or oropharynx SCC early onset. These findings present, for the first time, preliminary evidence that inherited abnormalities related to CASP9 c.-1339A>G and CASP3 c.-1191A>G SNPs are determinants of HNSCC risk and clinical aspects.

X-ray cross-complement 1 gene polymorphisms (Arg399Gln and Arg194Trp) in patients with acute myeloid leukemia

Background Acute myeloid leukemia (AML) is a clonal disorder characterized by acquisition of somatic mutations in hematopoietic progenitors leading to disruption of differentiation. X-ray cross-complement 1 (XRCC1) gene is a key component of the base excision repair pathway that may be involved in the repair of SS-DNA breaks. Polymorphisms in DNA repair genes may affect the DNA repair capacity and modulate cancer susceptibility by means of gene–environment interactions. This study aimed to evaluate the association between XRCC1 gene polymorphisms and the risk of development of AML and their impact on patients’ outcome. Materials and methods This study was conducted on 92 adult patients with AML of different FAB subtypes before induction of chemotherapy. They were selected from the Oncology Center Mansoura University, Egypt. Ninety-two healthy individuals served as a control group. Results The data obtained after the XRCC1 gene polymorphism study revealed that the Trp194Trp genotype and Trp allele showed higher frequency in AML cases compared with the control group. In addition, they were associated with a significant high risk of AML development within healthy participants (P=0.04). No significant differences were found in rs1799782 and rs25487 genotypes and alleles between cases and controls. Also, there was significant difference in overall survival in cases with XRCC1 Trp194Arg genotypes (P=0.048) and cases with Trp194Arg+ Trp194Trp (P=0.023) when compared with those with the Arg194Arg genotype. Conclusion Individuals with mutant Trp194Trp allele had a higher risk to develop AML and that the Trp194Arg+Trp194Trp genotype could predict poor prognosis in AML patients. This suggests XRCC1 polymorphism to be a novel target for new effective therapies of AML.

Genetic variant in miR-21 binding sites is associated with colorectal cancer risk.

Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3ʹ‐untranslated regions (UTRs). MicroRNA‐21 (miR‐21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR‐21 and colorectal cancer risk has not been widely investigated. A case‐control study including 1147 patients and 1203 controls was performed to evaluate the association of SNPs in miR‐21 binding sites and colorectal cancer risk. Dual‐luciferase reporter assays and functional assays were performed to evaluate the effects of miR‐21. The SNP rs6504593 C allele conferred an increased risk of colorectal cancer compared with the T allele in an additive model (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04‐1.36, P = 0.011). Dual‐luciferase reporter assays demonstrated that the rs6504593 T allele negatively post‐transcriptionally regulated IGF2BP1 by altering the binding affinity of miR‐21. Additionally, colorectal cancer cells transiently transfected with miR‐21 mimics promoted cell proliferation and suppressed apoptosis, whereas inhibition of miR‐21 decreased cell growth. These data suggest that the miR‐21 binding site SNP rs6504593 in the IGF2BP1 3ʹ‐UTR may alter IGF2BP1 expression and contribute to colorectal cancer risk.

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53± murine model

ABSTRACTThe Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To understand the role of WASp in tumorigenesis, we bred WASp+, WASp−, and WASp-XLN mice onto tumor susceptible p53+/- background and sub-lethally irradiated them to enhance tumor development. We followed the cohorts for 24 weeks and tumors were characterized by histology and flow cytometry to define the tumor incidence, onset, and cell origin. We found that p53+/-WASp+ mice developed malignancies, including solid tumors and T cell lymphomas with 71.4% of survival 24 weeks after irradiation. p53+/-WASp− mice showed lower survival rate and developed various early onset malignancies. Surprisingly, the p53+/-WASp-XLN mice developed malignancy mostly with late onset, which caused delayed mortality in this colony. This study provides evidence for that loss-of-function and gain-of-function mutations in WASp influence tumor incidence and onset.

Abstract 1220: Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant

Abstract Genome-wide association studies (GWAS) have identified genetic variants that may significantly modulate breast cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; often, it is not even clear whether the GWAS variants are functional themselves or just genetically linked to other functional variants. We here provide an integrated method for identifying functional regulatory variants associated with breast cancer and their target genes by combining the analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) systematically utilizing haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to the breast cancer susceptibility region in 5p12 demonstrates that the GWAS risk allele rs4415084-T is correlated with higher expression levels of the protein-coding gene MRPS30 and lncRNA RP11-53O19.1. We propose that an intergenic SNP, in linkage disequilibrium (LD) with the GWAS SNP rs4415084, is the predicted functional SNP. We provide multiple levels of evidence that the risk allele of the predicted functional SNP, in phase with the GWAS risk allele rs4415084-T, creates a GATA3 binding motif within a regulatory element, resulting in differential GATA3 binding and chromatin accessibility, which thereby promote the transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the risk SNP's role in modulating mitochondrial activities in breast cancer. Our computational framework can be extended to facilitate the rapid functional characterization of other genetic variants modulating cancer susceptibility and provides an effective way of integrating GWAS results with high-throughput genomic and epigenomic data. Citation Format: Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S. Song. Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1220.

Integrative Genomic Analysis Predicts Causative Cis-Regulatory Mechanisms of the Breast Cancer-Associated Genetic Variant rs4415084.

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here, we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci, a modified version of allele-specific expression that systematically utilizes haplotype information, transcription factor (TF)-binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1 We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2 = 0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3-binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.Significance: Unification of GWAS results with information from high-throughput genomic and epigenomic profiles provides a direct link between common genetic variants and measurable molecular perturbations. Cancer Res; 78(7); 1579-91. ©2018 AACR.

The miR-608 rs4919510 polymorphism may modify cancer susceptibility based on type.

Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00-1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted.

Cancer Immunoprevention and Public Health.

The power of cancer immune surveillance has been documented beyond doubt, and the successful exploitation of immune response to cancer has started a new era in the war against cancer. Cancer biologists have recognized immunoevasion as an emerging hallmark in addition to the six hallmarks of cancer. Besides the natural connection between the immune system and cancer development, most established environmental risk factors are now known to interfere with immune surveillance mechanisms. Genetic variations regulating immunity may also modulate cancer susceptibility, but evidence for this is currently limited. Molecular cross talk linking “immune” and “genomic” surveillance pathways has been characterized. It appears that immune mechanisms may contribute to the effects of common cancer risk factors. We provide an updated overview of evidence for cancer immune surveillance, cancer risk factors interfering with it, and interventions to enhance cancer immune surveillance as tools to complement ongoing vaccine development efforts for cancer immunoprevention. Although there is a lot of support for cancer immunoprevention with simple lifestyle modifications from observational studies, there is an urgent need for clinical trials to establish the effectiveness of this approach for public health benefits.

New concept of the Axin2 rs2240308 polymorphism and cancer risk: an updated meta-analysis

Previous meta-analyses reported that the variant Tallele of Axin2 rs2240308 is associated with adecreased cancer risk. However, more recent findings have been inconsistent. Therefore, we carried out an updated meta-analysis to examine whether thispolymorphismis still associated with adecreased cancer risk. Twelve articles, including 14 case-control studies (2,215 cases and 2,481 controls), were included in our study. Surprisingly, different from previous meta-analyses, no significant association between Axin2 rs2240308polymorphismand cancer risk was observed (dominant model: OR=0.85; 95% CI=0.68-1.06). In further stratified analyses, rs2240308 was significantly associated with adecreased cancer risk only in Asians (dominant model: OR=0.76; 95% CI=0.66-0.88), while for Caucasians the variant showed no significant association with cancer risk (dominant model: OR=1.09; 95% CI=0.67-1.76). Moreover, the rs2240308 variant exhibited asignificant association with adecreased risk of lung cancer and prostate cancer. These findings provided new evidence that differed from previous meta-analyses; Axin2 rs2240308 may not modify general cancer susceptibility. Similar with previous meta-analyses, our analysis indicated that Axin2 rs2240308 may modify cancer susceptibility in an ethnicity- and/or type-specific manner. These findings indicate that further replication studies with large sample sizes are warranted to re-evaluate the relationship between Axin2 rs2240308 and cancer risk, especially in Caucasians.

Mitochondrial genetics and cancer

The first modern human, the Mitochondrial Eve, was traced back to Africa about 200,000 years ago, based on the variation in the mitochondrial DNA (mtDNA). An eruption of a super volcano, Mount Toba, in Sumatra 70,000 years ago may have led to a 'nuclear winter', followed by a 1,000-year ice age. This cold snap would have made life difficult; genetic evidence indicated a sharp reduction in population size around this time, reaching approximately 10,000 individuals. Once the climate started to improve, our ancestors recovered from this near-extinction event. The population expanded, and some courageous explorers ventured beyond Africa. Around 50,000 years ago some of these brave ancestors had successfully crossed the globe to South East Asia and Australia. Some of them settled in the Indonesian archipelago, forming the first settlement of prehistoric Indonesia. The second migration happened around 10,000 years ago, where a group of hunter-gatherers followed the now-submerged river systems that once ran from mainland Asia between the modern islands of Sumatera, Java, and Borneo. Then, around 4,000 years ago the third group of ancestors arrived. This agricultural community brought along their culture of pottery, plant cultivation, and animal domestication, co-inciding with the vast spread of Austronesian languages. Therefore, it is likely that the Indonesian archipelago hosts a wide range of linguistic, ethnic and genetic diversity. 1 Nowadays, the modern Indonesia is home to around 700 ethnic populations, each with distinct cultural and linguistic characteristics, representing vast genome diversity. Our ancestors’ decision to embark on a sea travel and take on its related lifestyle has influenced the development of susceptibility and resistance to various diseases observed today. During the prolonged travel, our ancestors were subjected to changes in global climate and geographic dynamic, which strongly influenced and shaped the genetic background of modern humans, including the mtDNA genome. Mitochondria, a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS). Adaptation to new environments that favor beneficial traits may have caused genetic risk differences that influence the crucial function of the mitochondria, consequently affecting many function in the cell. 2 The altered function of the mitochondria might act as an important factor for disease susceptibility across many human populations, i.e. mtDNA variation that grouped together forming a certain type/group (the mtDNA haplogroup) was reported to modulate cancer susceptibility 3-5 and resistance 6 in Chinese population. Cancer cells are characterized in general by a decrease of mitochondrial respiration and OXPHOS, a consequence of disruptive mtDNA mutations commonly found in cancer cells, and thus one could say that the growth of cancer cells is directly limited by energetics. 7 In order to survive, cancer cells must modify their mitochondrial physiology to optimize energy production to their changing environments. There are two types of advantageous mtDNA mutation in cancer cells: mutations that impair OXPHOS and serve to stimulate neoplastic transformation, and those that facilitate cancer cell adaption to changing bioenergetics environments. 8 These mtDNA mutations would eventually lead to an enhanced generation of reactive oxygen species (ROS), which can act both as mutagens and cellular mitogens, and contribute directly to cancer progression. 7 Therefore, it can be concluded that mitochondrial alterations are critical for cancer initiation, promotion, and metastasis (Fig 1). Figure 1. Integrated mitochondrial paradigm to explain genetic and phenotypic complexities of metabolic and degenerative disease, aging, and cancer. Top three arrows : factors that have impact on mitochondrial OXPHOS robustness, risk for developing disease symptoms. Central oval arrows : pathophysiological basis of disease processes and the basis of disease progression. Lower five arrows : summarized disease categories and phenotypic outcomes of disturbed mitochondrial energy transformation. Bottom arrow : effect of the problematic accumulation of somatic mtDNA mutations resulting in delayed onset and a progressive course of diseases and aging. Right arrow : clinical problems that can result from reduced energy production in the most energetic tissues: the brain, heart, muscle, and kidney. Left arrow : indicates the metabolic effects of mitochondrial dysfunction, which result in the perturbation of the body’s energy balance. Lower right arrow : mitochondrial alterations are critical for cancer initiation, promotion, and metastasis . Lower left arrow : the hypothesized inflammatory and autoimmune responses that may result from chronic introduction of mitochondria’s bacteria-like DNA and N-formylmethionine proteins into the bloodstream. 9

Quantitative assessment of polymorphisms in H19 lncRNA and cancer risk: a meta-analysis of 13,392 cases and 18,893 controls.

H19 refers to a long non-coding RNA (lncRNA) that functions as an oncogenic molecule in different cancer cells. Genetic variants of H19 may affect the activity of certain regulatory factors, which subsequently regulate the aberrant expression of H19. This feedback loop might be one of the underlying mechanisms influencing tumour susceptibility and prognosis. Although there have been several recent studies that examined possible links between polymorphisms in H19 and cancer risk, the results have been inconclusive. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms (rs2107425, rs2839698 and rs217727) and cancer risk. Ten studies comprising 13,392 cases and 18,893 controls were included in the study. Overall, the variant T allele of rs2107425 correlated with a significantly decreased risk of developing cancer (dominant model: OR = 0.86; 95% CI = 0.76–0.98). In addition, a marginally significant association between the rs2839698 and cancer risk was observed (dominant model: OR = 1.09; 95% CI = 0.99–1.20). After stratification for ethnicity, it became apparent that Asians with the variant A allele of rs2839698 exhibited a significantly higher risk of developing cancer (dominant model: OR = 1.11; 95% CI = 1.01–1.23). Interestingly, the rs2839698 variant was also significant associated with an increased risk of cancers of the digestive system (dominant model: OR = 1.23; 95% CI = 1.08–1.41). These findings provided evidence that H19 rs2107425 may modify general cancer susceptibility, while rs2839698 may modify cancer susceptibility based on ethnicity and type. Further experimental studies to evaluate the limits of this hypothesis are warranted, and future functional studies are required to clarify the possible mechanisms.

Association of polymorphisms in Dickopff (DKK) gene towards modulating risk for lung cancer in north Indians.

To investigate the association between the genetic variants of DKK4 (rs2073664), DKK3 (rs2291599, rs3206824 and rs7391689) and DKK2 (rs447372, rs419558 and rs17037102) and lung cancer predisposition in north Indians. A total of 600 subjects were genotyped using PCR restriction fragment length polymorphism technique. Association analysis was carried out using logistic regression approach. DKK3 rs7396187 showed a protective effect (p = 0.01). Subjects with heterozygous genotype of DKK2 rs17037102 and rs419558 showed an increased risk. The variant genotype of the genotypic combination, DKK3 rs3206824 and DKK2 rs419558 showed a twofold increased risk (p = 0.008). Lung cancer risk increased four-times in subjects with variant genotype of all the three DKK2 variants. DKK2 is certainly playing a crucial role in modulating cancer susceptibility.

Association between the ERCC1 Polymorphisms and Glioma Risk: A Meta-Analysis of Case-Control Studies

Objective: Polymorphisms in DNA repair genes have been shown to influence DNA repair processes and to modify cancer susceptibility. Published data regarding the association between excision repair cross-complementing rodent repair deficiency complementation group1 (ERCC1) polymorphisms and glioma risk have been inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and glioma risk, a meta-analysis was performed. Methods: Data was collected in PubMed and EMBASE, with the last search up to 30 th August 2013. A total of 6 studies were identified with 2642 cases and 3669 controls for ERCC1 C8092A polymorphism, and 4 studies were identified with 1390 cases and 1546 controls for ERCC1 C118T polymorphism. All of the statistical analyses were performed using statistical data 10.0. Results: The combined results showed that ERCC1 C8092A polymorphism was associated with glioma risk (additive model: OR = 1.10, 95% CI 1.02 - 1.20; recessive model: OR = 1.51, 95% CI 1.24 - 1.85; co-dominant model AA vs. CC: OR = 1.52, 95% CI 1.24 - 1.86). As for ethnicity subgroup analysis, ERCC1 C8092A polymorphism was associated with increased glioma risk among Chinese(additive model: OR = 1.15, 95% CI 1.01 - 1.30; recessive model: OR = 1.34, 95% CI 1.02 - 1.75; AA vs. CC: OR = 1.37, 95% CI 1.03 - 1.81), and so among Caucasian except additive model(recessive model: OR = 1.75, 95% CI 1.31 - 2.34; co-dominant model AA vs. CC: OR = 1.70, 95% CI 1.27 - 2.29). No evidence of an association of ERCC1 C118T polymorphism with glioma was found. Conclusion: The meta-analysis suggested that ERCC1 C8092A polymorphism might be associated with the increased risk of glioma, whereas ERCC1 C118T polymorphism might have no influence on the susceptibility of glioma.