Both the central role of miRNAs as regulators of translation and their functional significance in cancer pathogenesis have been established some time ago, whereas the relationships between genetic variation in genes of the miRNA regulatory pathway and cancer risk have only begun to be explored recently . As of today, over 30 epidemiologic studies were carried out that focus on the importance of miRNA-related SNPs in cancer susceptibility and therapeutic and clinical outcome in patients with a wide range of solid cancers (summarized in Table 1).
Breast cancer is the leading cause of cancer-related death in women and the second most common cancer in the world after lung cancer. As up to 10% of the total number of women diagnosed with breast cancer report a family history, miRNAs [9, 10] could represent a promising new class of potentially susceptibility genes.
The most frequently studied SNP is rs11614913 in the pre-miRNA region of miR-196-a2 which was first identified by Hu et al. (2008) in a case-control study of 1009 breast cancer cases and 1093 cancer-free controls in a population of Chinese women. Although most miRNAs repress target translation, hsa-mir-196 was found recently to direct mRNA cleavage of its target, Hoxb8 . The hsa-mir-196a2 rs11614913:T>C variant genotype is associated with significantly increased risk of breast cancer . These observations were further validated by Hoffman et al. (2010) who performed a screening of genetic variants in 15 miRNA genes in a study of 441 cases and 479 controls and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913:C>T) is significantly associated with decreased breast cancer risk. Moreover, by delivering expression vectors containing either wild-type or mutant precursors of miR-196a-2 into breast cancer cells, they have showed that this variant leads to the less efficient processing of the miRNA precursor to its mature form as well as to its diminished capacity to regulate target genes . On the contrary, the study conducted by Catucci et al. (2010) on 1894 German and Italian familial breast cancer cases suggested a lack of association between SNPs rs11614913 and both breast cancer risk and age at breast cancer onset .
A G to C polymorphism (rs2910164) located within the sequence of a miR-146a precursor, which leads to a change from a G:U pair to a C:U mismatch in its stem region was primarily studied by Shen et al. (2008) . The predicted miR-146a target genes include BRCA1 and BRCA2, that is the key breast and ovarian cancer susceptibility genes. To examine whether rs2910164 plays any role in breast and ovarian cancer, the associations between this polymorphism and the age at diagnosis were studied in 42 patients with familial breast cancer and 82 patients with familial ovarian cancer. Breast cancer patients who had at least one miR-146a variant allele were diagnosed at an earlier age than women with no variant alleles (median age 45 versus 56 years, P = 0.029) and ovarian cancer patients who had at least one miR-146a variant allele were diagnosed at younger age than women with no variant allele (median age 45 versus 50 years, P = 0.014) . Unfortunately, the association of rs2910164 and breast cancer was not confirmed in further larger studies by Hu et al. (2008) and Catucci et al. (2010).
An SNP in the pre-miRNA region of hsa-mir-499 (rs3746444:A>G) was detected in a cell line of invasive breast cancer. Therefore, it is biologically plausible that these polymorphisms of hsa-mir-499 may play a role in the development of breast cancer. Hu et al. (2008) reported that the hsa-mir-499 variant genotype is associated with significantly increased risk of breast cancer; on the contrary, Catucci et al. (2010)  reports lack of association among their total of 1894 breast cancer cases who were negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. The obvious inconsistency of these observations could be explained by different ethnicity of investigated populations.
SNP rs895819, located in pre-miR-27a, was selected for an association study by systematic approach based on the scanning for SNPs located in the recently identified breast cancer-relevant miRNA genes (including pre-miRNAs and about ±200 bp flanking regions) by sequencing of these regions. In a group of 1217 German familial breast cancer patients and 1422 unrelated healthy German women, Yang et al. found that the G allele of rs895819, located in the terminal loop of a pre-miR-27a oncogene, was associated with the reduced familial breast cancer risk (P = 0.0215) . Significance of the rs895819 was further confirmed in a most interesting study by Kontorovich et al., who hypothesized that aberrant gene silencing by miRNA may affect mutant BRCA penetrance: to test this presumption, the frequency of 42 SNPs within predicted miRNA-binding sites or miRNA precursors was determined and compared in 363 BRCA1 and 125 BRCA2 mutation carriers in high-risk Jewish women. In addition to other important outcomes of this study, the authors report that BRCA2 mutation carriers had a significantly higher risk of developing breast cancer when being the TT homozygotes compared to T/C heterozygotes of pre-miR-27a (rs895819; P = 0.013) and when carrying AC alleles compared to the AA carriers of miR-423 (rs6505162; P = 0.021). This study provides preliminary evidence for another regulatory level of deleterious mutations penetrance in cancer predisposition genes .
In addition to the polymorphisms within miRNA and pre-miRNA sequences, several SNPs in miRNAs binding regions 3′-UTR of coding genes were also identified as novel biomarkers of breast cancer susceptibility.
Brendle et al.  examined the effect of SNPs in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer risk and clinical outcome. Six SNPs were genotyped in 749 Swedish breast cancer cases with detailed clinical data and the follow-up included up to 15 years of study with 1493 matched controls. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours (OR 2.09; 95% CI 1.19–3.67). The A allele carriers had a worse survival rate compared to the carriers of the wild-type genotypes. None of the SNPs were significantly associated with breast cancer risk .
Tchatchou et al.  reported significant association of a variant (rs2747648: C>T) affecting a miRNA target site in the oestrogen receptor 1 (ESR1). Age stratification of the cases in this study revealed that the association was stronger in pre-menopausal women (OR 0.60; 95% CI 0.41–0.89; P = 0.010). Furthermore, the effect was stronger in high-risk familial cases (OR 0.42; 95% CI 0.25–0.71; P = 0.0009). According to in silico analysis, rs2747648 affects the binding capacity of miR-453, which is increased in the presence of the C allele. By contrast, the T allele attenuates the binding of miR-453, which may lead to a reduced miRNA-mediated ESR1 repression and consequently to higher ESR1 protein levels and an increased breast cancer risk .
SET8 methylates TP53 and regulates genome stability. Song et al.  evaluated the SNP (rs16917496) within the miR-502 seed binding region in the 3′-UTR of the SET8 gene in a case-control study on 1110 breast cancer cases and 1097 controls. The SET8 CC genotype was independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (52.2 years for TT, 51.4 for TC and 49.5 for CC) .
Bone morphogenetic protein receptor type-1 (BMPR1B) binds bone morphogenetic proteins (BMP) that are multifunctional signalling molecules that belong to the TGF-β superfamily and were first identified based on their ability to form bone tissue the extraskeletal sites. miR-125b negatively regulates BMPR1B and C/T allelic variation (rs1434536) within the target site, disrupting the regulation by miR-125b, increasing BMPR1B expression and ultimately elevating disease risk . Findings of Saetrom et al.  indicated in a cohort of 428 breast cancer patients and 1064 controls indicate that carriers of the TT genotype in the BMPR1B gene are at higher breast cancer risk .
There are also several experimentally evaluated miRNA-related SNPs lacking association with breast cancer risk or clinical outcome rs12983273 in miR-373 , rs3807348 in miR-335 , rs731085 in let-7a-3  and rs2292832 in miR-149 .
Several genome-wide profiling studies described dysregulation of miRNAs in colorectal cancer (CRC) tissue and blood serum [11, 12]. A number of experimental studies on these miRNAs revealed insight into miRNA-mediated regulatory links to well-known oncogenic and tumour suppressor signalling pathways. The polymorphisms within the miRNA sequences and binding regions within 3′-UTRs of their mRNA targets were reported to be novel CRC risk factors .
By analysing human gene sequences obtained from the public database (http://genome.cse.ucsc.edu/), Kim et al.  found that six miRNA regulation genes (AGO1, AGO2, TARBP2, TNRC6A, TNRC6C and EXPORTIN5) have mononucleotide repeats with seven or more nucleotides in the coding sequences which could be potential targets for frameshift mutation in cancers with microsatellite instability (MSI) . Mutations in analysed genes except the AGO1 were detected in 27% of CRC samples. Significant differences in mutation frequency between the cancers with MSI-H (19/58), MSI-L (0/32) and MSS (0/90) indicated that association of the mutations with CRC could be MSI-H specific. It seems that frameshift mutations of these genes could cause alterations of miRNA regulation and could contribute to the development of CRC indicating MSI-H phenotype .
A study of Lee et al.  included 426 consecutive Korean patients with surgically treated CRC: 40 polymorphisms in miRNA-related genes were determined. In a univariate analysis, the progression-free survival of the patients with the combined miR-492 C/G and G/G genotype was significantly worse than that of the patients with the mir-492 C/C genotype (rs2289030; P = 0.0426), however there was no difference in the overall survival .
Pioneering design in the field of research of miRNAs-associated SNPs was presented in the study by Landi et al. , who selected 3′-UTRs of 104 genes as candidates for CRC and identified putative miRNA-binding sites by specialized algorithms (PicTar, DianaMicroT, miRBase, miRanda, TargetScan and microInspector). Fifty-seven SNPs were identified in miRNA-binding sites and evaluated for their ability to affect binding of miRNA to its target, by assessing the variation of Gibbs free energy between the two alleles of each SNP. A total of eight common SNPs were identified and further investigated in a case-control association study. The study was carried out on a series of 968 cases and 697 controls from the Czech Republic, a population with the highest worldwide incidence of CRC. Statistically significant associations were found between CRC risk and variant alleles of CD86 and INSR genes. These observations are the first to report positive associations between SNPs in miRNA-binding regions and cancer risk .
Recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). Zhang et al.  have tested the hypothesis whether SNP in a let-7 microRNA complementary site (lcs6) in the KRAS 3′-UTR may be associated with a clinical outcome in 130 KRAS wild-type (KRASwt) mCRC patients enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). KRAS let-7 lcs6 SNP was found to be related to object response rate (ORR) in mCRC patients whose tumours had KRASwt. The 12 KRASwt patients harbouring at least a variant G allele (TG or GG) had a 42% ORR compared to a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02). KRASwt patients with TG/GG genotypes also presented with a trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to the individuals with TT genotypes .
The discovery of biomarkers and their application in conjunction with traditional cancer diagnosis, staging and prognosis could substantially improve timely diagnosis and patient care. However, despite the efforts made to date, reliable markers are still missing and prognosis of the disease remains poor. In case of lung cancer, miRNA expression profiles and specific miRNAs have been shown to correlate with tumoural tissue and survival of lung adenocarcinomas [13, 14].
Tian et al.  conducted a study focusing on significance of four miRNA SNPs (miR-146a rs2910164, miR-499 rs3746444, miR-149 rs2292832, miR-196-a2 rs11614913) as potential risk factors of non–small cell lung cancer (NSCLC) in a case-control study of 1058 incident lung cancer patients and 1035 cancer-free controls from a Chinese population. The miR-196a2 rs11614913 variant homozygote CC was associated with a 25% increase in lung cancer risk compared to their wild-type homozygote TT and heterozygote TC. However, no significant effects were observed in case of the association between the three remaining SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to susceptibility to lung cancer .
The same research group evaluated in detail the association between the same SNPs and the survival of patients with NSCLC . As they assumed that disease susceptibility was inherited as a recessive phenotype, they found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in 556 individuals with NSCLC (107 patients in the validation set). Specifically, the survival rate was significantly lower in case of CC homozygotes. Binding assays revealed that rs11614913 can affect binding of mature hsa-mir-196a2 to its target mRNA. This is the first study to describe miRNA SNPs and NSCLC outcome on a large study population size with high statistical power (if α = 0.05, based on the data set for hsa-mir-196a2 rs11614913, an 80% power to detect an HR of 1.41 was reached) .
The let-7 family of miRNAs seems to play a key role in lung cancer: their levels are decreased in NSCLC; the lower levels are biomarkers of poor outcome; these miRNAs regulate multiple important oncogenes involved in lung cancer, including KRAS, and they inhibit growth of lung cancer cell lines both in vitro and in vivo . The aim of the seminal study by Franck J. Slack's group from Yale was to identify SNPs, which could potentially modify let-7 binding as well as to assess the effects of these SNPs on target gene regulation and the risk of NSCLC. let-7 complementary sites (lcs) were sequenced in the KRAS 3′ untranslated region in 74 NSCLC cases to identify mutations and SNPs correlating with NSCLC. The allele frequency of a previously unidentified SNP at lcs6 was characterized in 2433 people (representing 46 human populations). The frequency of the variant allele was 18.1–20.3% in NSCLC patients and 5.8% in worldwide populations. The association between this SNP and the risk of NSCLC was also investigated in a case-control study of lung cancer cases from the New Mexico that showed a 2.4-fold increased risk (95% CI 1.1–4.6; P = 0.02) for NSCLC cancer. Functionally, the variant allele resulted in KRAS overexpression in vitro. The lcs6 variant allele in a KRAS miRNA complementary site was significantly associated with increased risk of NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility .
Given the functionality of lcs6, Nelson et al.  evaluated the hypothesis that this SNP is associated with the occurrence of KRAS mutation as well as survival in a cohort of 218 NSCLC patients. No association was reported between the lcs6 KRAS polymorphism and KRAS mutational status (codon 12). Furthermore, no association between lcs6 SNP and NSCLC patients survival rate was observed .
Recently, many studies suggested that miRNAs are involved in prostate cancer carcinogenesis [7, 8, 17]. To explore whether the intensively studied polymorphism rs2910164 (G>C) in miR-146a plays any role in prostate cancer, Xu et al.  analysed the association between miR-146a polymorphism and risk of prostate cancer in 251 patients and 280 controls from a southern Han Chinese population. The patients carrying CC homozygote genotype had a 0.65-fold reduced risk of the disease (95% CI 0.43–0.99) in comparison with those carrying GG/GC genotypes (P = 0.03), and the C allele displayed a lower prevalence of prostate cancer compared to the G allele (OR 0.73; 95% CI 0.57–0.94, P = 0.01). Moreover, miR-146a quantification showed that homozygous carriers of the C-variant had significantly decreased miRNA level compared to the carriers of the GG/GC genotype. Based on these data, it seems that rs2910164 in miR-146a contributes to the genetic predisposition to prostate cancer .
Renal cell carcinoma
Horikawa et al.  hypothesized that genetic variations in miRNA genes and miRNA machinery genes could be associated with the risk of renal cell carcinoma (RCC). Forty SNPs in 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes were genotyped in 279 Caucasian patients with RCC and 278 matched controls. Two SNPs in the GEMIN4 gene were significantly associated with altered RCC risk. The variant-containing genotypes of Asn929Asp (rs2740348) and Cys1033Arg (rs7813) exhibited significantly reduced risks. A combined unfavourable genotype (UG) analysis was conducted including five promising SNPs (DICER1 [rs3742330], AA; AGO1 [rs595961], AA; GEMIN4 [rs2740330], GG; GEMIN4 [rs7813], TT; GEMIN3 [rs197412], TC+CC; GEMIN3 [rs197388], TA+AA) showing at least a borderline significant association with the risk of the disease. Compared to the low-risk reference group with one UG, the median-risk (with two UGs) and high-risk (with three to five UGs) groups exhibited a 1.55-fold (95% CI 0.96–.50) and 2.49-fold (95% CI 1.58–3.91) increased risk of RCC, respectively (P for trend < 0.001). This data suggest that SNPs in miRNA-machinery genes may affect RCC susceptibility .
The same research team has evaluated the effects of the similar SNPs on survival and recurrence among renal cell RCC patients. When the SNPs were analysed separately, seven SNPs were found to be significantly associated with RCC survival and five with recurrence . The most significant associations were SNPs in GEMIN4 with the variant alleles of both rs7813 and rs910925 associated with 1.74-fold (95% CI 1.15–2.62) increased risk of death, whereas the variant allele of rs3744741 conferred a decreased risk of death (HR 0.39; 95% CI 0.19–0.77). Several SNPs belonging to the pre-miRNA were identified to be significantly associated with RCC recurrence. Haplotypes of DICER and DROSHA were also associated with altered survival of the patients and recurrence of the disease. Compared to the patients carrying zero to two UGs, those individuals carrying three to five and six and more UGs had an increased risk of death with a HR of 2.49 (95% CI 1.24–5.00) and 6.66 (95% CI 2.49–17.86), respectively, with a significant dose–response trend (P for trend < 0.001). This data strongly suggest that miRNA-related SNPs may impact the recurrence and survival in RCC patients .
In cervical cancer, miR-218 can target laminin-5 β3 (LAMB3), but it is suppressed by HPV-16 E6 protein. Because laminin-5 is required in RAS and NF-κB blockade induced tumourigenesis of human squamous cell carcinoma and because it is a marker of invasiveness in cervical lesions, Zhou et al.  hypothesized that SNPs in pri-miR-218 rs11134527 and LAMB3 rs2566 may be individually and/or jointly involved in pathogenesis of cervical. Zhou et al. genotyped these two SNPs in a case-control study of 703 cervical cancer cases and 713 cancer-free controls of Chinese origin. In logistic regression analyses, the variant GG homozygote of pri-miR-218 rs11134527 was associated with the decreased risk of cervical cancer in comparison to the AA genotype, whereas the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer, compared to the wild-type CC genotype. A significant dose–response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend = 0.0006) .
In a study by Liang et al. , the total of 26 SNPs in miRNA processing genes and miRNA-binding sites were analysed in 339 ovarian cancer cases and 349 healthy controls to assess association with cancer risk, overall survival and treatment response. Thirteen polymorphisms were found to have significant association with risk, whereas the most significant were two linked SNPs (r(2) = 0.99)), rs2740351 and rs7813 in GEMIN4.
In a large investigation by Permuth-Way et al. , a total of 318 SNPs in 18 genes were evaluated among 1815 epithelial ovarian cancer cases and 1900 controls, followed up by a replicative joint meta-analysis of data from an additional 2172 cases and 3052 controls. Of 23 SNPs from nine genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated six SNPs from the DROSHA, FMR1, LIN28 and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (P = 0.015) and the authors conclude that based on their observations, variants in LIN28B and possibly other miRNA biogenesis genes may influence susceptibility to epithelial ovarian cancer.
To expand knowledge regarding the new SNP and biological function of miR-27a, Sun et al.  designed a study to determine whether A/G polymorphism (rs895819) within mir-27a is associated with a risk of gastric cancer. Authors also investigated miR-27a and its target gene Zinc finger and BTB domain containing 10 (ZBTB1) expression in consideration of the genotype . In a case-control study on 304 gastric cancer cases and 304 cancer-free controls, they observed that the patients with variant genotypes (AG + GG) showed a significantly increased risk of gastric cancer compared to AA carriers (adjusted OR 1.48; 95% CI 1.06–2.05; P = 0.019). A significant association of hsa-mir-27a variant genotypes with lymph node metastasis was also observed. Further functional analyses indicated that variant genotypes might also be responsible for elevated miR-27a levels and reduced ZBTB10 mRNA .
The most frequently studied SNP in miRNAs, rs11614913 in miR-196a-2, was also studied in the gastric cancer. Peng et al.  conducted a hospital-based case-control study on 213 gastric cancer patients and 213 age- and sex-matched controls of Chinese origin. They found a significantly increased risk of gastric cancer in patients with the variant homozygote CC of miR-196a-2 in comparison with the wild-type homozygotes TT and CT heterozygote (adjusted OR 1.57; 95% CI 1.03–2.39; P = 0.038). Stratified analyses indicated that the variant homozygote CC genotype had a strong association with the lymph node metastasis of gastric cancer (adjusted OR 2.25, 95% CI 1.21–4.18, P = 0.011). These findings suggest that genetic variants within both miR-196a-2 and miR-27a could play an important role in the development and progression of gastric cancer .
The first study to evaluate the significance of SNPs in miRNA processing pathway genes in bladder cancer predisposition was published by Yang et al. . In this case-control study, the authors tested the hypothesis that common sequence variants in genes of miRNA and miRNA biogenesis pathway affect susceptibility to bladder cancer. To better understand this effect, the total of 41 SNPs from 24 miRNA genes were genotyped in a study conducted on 746 Caucasian patients with bladder cancer and 746 matched controls. The homozygous variant genotype of a non-synonymous SNP in the GEMIN3 gene (rs197414) was associated with significantly increased risk of bladder cancer. Several additional miRNA-related SNPs, which showed a borderline significant association with risk of bladder cancer were also identified. To assess the cumulative effects of the promising SNPs, we performed a combined UG analysis that included all SNPs showing at least a borderline statistical significance. Compared to the low-risk reference group with less than two UGs, the medium-risk group with two UGs exhibited a 1.29-fold (0.92–1.81) increased risk, whereas the high-risk group with more than two UGs exhibited a 1.92-fold (1.36–2.71) increased risk (P < 0.0001) .
The associations between oesophageal cancer risk and 41 potentially functional SNPs in 26 miRNA-related genes in a case-control study on 346 Caucasian oesophageal cancer patients (85.5% with oesophageal adenocarcinoma) and 346 frequency-matched (age, gender and ethnicity) controls were explored in a study by Ye et al. . Seven SNPs were significantly associated with oesophageal cancer risk. The most notable finding was that the rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 (95% CI 0.51–0.80; P for trend < 0.0001). A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of oesophageal cancer (OR 0.65; 95% CI 0.42–0.99). An analysis to further evaluate the cumulative effects of the promising (risk associated) combined UG SNPs was also performed. In comparison with the low-risk group (fewer than three UGs), the medium-risk group (three UGs) had a 2.00-fold (95% CI 1.31–3.08) increased risk and the high-risk group (three UGs and more) had a 3.14-fold (95% CI 2.03–4.85) increased risk (P for trend < 0.0001) .
Promising findings suggesting that functional rs2910164 in pre-miR-146a could contribute to susceptibility to oesophageal squamous cell carcinoma (ESCC) and clinical outcome were reported by the group of Guo et al.  in their case-control study on 444 sporadic ESCC patients and 468 matched cancer-free controls from a Han Chinese population. Compared to CC variant genotype of rs2910164, the GG genotype was associated with increased risk of ESCC (OR 2.39; 95% CI 1.36–4.20). Among smokers, the risk of GG genotype of rs2910164 was more pronounced (OR 3.17; 95% CI 1.71–4.46). In the stratification analyses, a strong correlation was identified between rs2910164 C/G variant and the clinical TNM stage (P < 0.01) .
The first association study of miRNA polymorphisms and hepatocellular cancer (HCC) involved 479 HCC and 504 control patients. Xu et al.  found that the genotype distribution of miR-146a polymorphism rs2910164 in HCC cases was significantly different from that in control patients (P = 0.026). The results revealed that male individuals with GG genotype were twice as susceptible to HCC (P = 0.034) compared to those with CC genotype. When investigating the influence of this SNP on production of mature miR-146a, G-allelic miR-146a precursor displayed increased production of mature miR-146a compared to the C-allelic one .
Recent studies have implied that the rs11614913 SNP in miR-196-a2 is associated with susceptibility to a broad spectrum of solid tumours. To assess whether this SNP is associated with susceptibility to and clinicopathologic characteristics of the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were studied, and a miR-196-a2 polymorphism was genotyped . In this study, there was no significant association between miR-196-a2 SNP and the risk of HBV-related HCC in all patients; however, the risk of HCC was significantly higher with miR-196-a2 rs11614913 CC genotype or C allele compared to those with the TT genotype or T allele in male patients (P = 0.031 and 0.046, respectively). Moreover, the T allele was significantly more frequent in male HCC patients with lymphatic metastasis (P = 0.03) .
Gao et al.  predicted polymorphisms falling in miRNA-binding regions of HCC genes. Considering the effects of IL-1α, not only in carcinogenesis, tumour growth and invasiveness, but also in terms of interaction patterns between malignant cells and the host's immune system, the authors selected an insertion/deletion (Indel) polymorphism (rs3783553) in the 3′-UTR of interleukin-1α (IL-1α) for a case-control study in a Chinese population. With samples from 403 HCC patients and 434 healthy control individuals, strong evidence of association was observed for the variant homozygote. This association was validated in a second independent case-control study with 1074 HCC patients and 1239 healthy control individuals. ‘TTCA’ insertion allele for rs3783553 disrupts a binding site for miR-122 and miR-378, thereby increasing transcription of IL-1α in vitro and in vivo. These findings suggest that functional polymorphism rs3783553 in IL-1α could contribute to HCC susceptibility .
Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found so far. In an association study of 608 PTC patients and 901 controls, marked differences in genotype distribution of rs2910164 in miR-146a (P < 0.001) were found, the GC heterozygotes being associated with an increased risk of developing PTC (OR 1.62, P = 0.001), and both homozygous states being protective with an odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P < 0.001) . Jazdzewski et al.  explain this interesting observation in another study of theirs by pointing out a mechanism based on the fact that GC heterozygotes differ from both GG and CC homozygotes by producing three mature microRNAs: one from the leading strand (miR-146a) and two from the passenger strand (miR-146a*G and miR-146a*C), each with a distinct set of target genes .
Moreover, the authors showed that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared to the G allele. This is followed by a similar decrease in the amount of each pre-miRNAs generated from the corresponding pri-miR-146a in an in vitro processing reaction. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signalling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC .
In gliomas, only one polymorphism within a mature miRNA sequence, specific rs11614913 gene variant of miR-196a, has ever been studied so far . The obtained data suggest that the CC genotype of miR-196a SNP is associated with decreased risk of glioma in the Chinese population (OR 0.74; 95% CI 0.56–0.98). Significant association was similarly observed between these genotype and risk of particular glioma subgroups: patients over 18 years (OR 0.73; 95% CI 0.55–0.98), male glioma patients (OR 0.69; 95% CI 0.48–0.99) and patients with high-grade glioma–glioblastoma (OR 0.58; 95% CI 0.37–0.91). In contrast to other solid cancers, such as lung cancer  and breast cancer [45, 46], data from glioblastoma cases showed an opposite association between miR-196a genotype and cancer risk, which could be explained by the diversity of tissue origin and subsequent characteristic molecular alterations in different types of cancer .