Genome-wide Association Study: Not so benign
Susceptibility to uterine fibroids, benign tumors that affect the health of many women, is linked to genes that are responsible for preserving genome integrity and promoting genitourinary development.
- McGill University, Canada
- Jewish General Hospital, Canada
The established consensus is that benign tumors do not become malignant and do not metastasize, but this does not mean they are not clinically important. Uterine leiomyomas are a perfect example. These tumors, which are commonly referred to as fibroids or myomas, affect up to 70% of women before menopause (Stewart et al., 2017), and cause multiple clinical problems, including excessive uterine bleeding, pelvic pain, infertility and miscarriage. Fibroids are also the leading cause of hysterectomy, and therefore incur substantial medical costs around the world (Soliman et al., 2015).
Even in this cancer genomics era, our knowledge of the processes underlying the growth of these tumors is limited. Although they derive from a single smooth muscle cell in the uterine wall, fibroids are a heterogeneous tumor group. Broadly, they can be divided into three main groups, the most common being fibroids with alterations in MED12 (a gene found on the X chromosome), followed by lesions that are deficient in an enzyme called fumarate hydratase, and lesions in which a protein called HMGA2 is overexpressed. Numerous risk factors contribute to fibroid development, including age, obesity, hormones, hypertension and ancestry, with African-American women at the top of the prevalence chart (Dvorská et al., 2017).
Multiple fibroids can occur as part of a hereditary syndrome called familial leiomyomatosis that is caused by germline mutations in the gene coding for fumarate hydratase. Moreover, and independent of familial leiomyomatosis, the first-degree relatives of affected women have a 2.5 times greater chance of developing fibroids than the general population. So, are there loci in the genome that are linked to a general susceptibility to leiomyomas? A handful of studies have explored this question and identified a few loci that are associated with a small increase in the risk of leiomyomas. However, these results are restricted to specific populations or have limited biological significance (Cha et al., 2011; Edwards et al., 2013; Hellwege et al., 2017). Now, in eLife, Lauri Aaltonen of the University of Helsinki and co-workers – including Niko Välimäki and Heli Kuisma as joint first authors – report how they have performed a genome-wide association study that sheds light on the development of leiomyomas (Välimäki et al., 2018).
The study was performed in five stages (Figure 1). In the first phase the researchers analyzed cases and controls from the UK Biobank, which resulted in a list of 50 candidate variants from 22 loci in the genome that might be associated with fibroids. These variants were single nucleotide polymorphisms (SNPs): that is, variants in which one nucleotide had been replaced by a different nucleotide. The researchers then computed the polygenic genomic risk score (GRS), which is a sum of the risk associated to each candidate variant, and validated the association of this score to fibroid development in an independent cohort from Helsinki. In the second phase the researchers combined the two populations in a case-control meta-analysis, which led to another seven candidate variants being identified (bringing the total to 57). The genomic risk score was recalculated in this second phase.
Figure 1
A genome-wide association study on leiomyomas.
The study performed by Välimäki et al. had five phases. (1) Discovery: regions along the genome were compared in 15,453 women with leiomyomas (the cases) and a control sample of 392,628 women from the UK Biobank to identify locations where the two sets of genomes differed. 50 variants (in the form of a SNPs; single nucleotide polymorphisms) at 22 loci were identified and used to compute a genomic risk score (GRS). (2) Meta-analysis: Välimäki et al. then validated the risk score obtained in the first phase by studying cases and controls from Helsinki. Combining the UK Biobank and Helsinki samples lead to the identification of another seven variants. The risk was also recalculated at the end of this phase. (3) Validation: The risk score was then validated in six different ethnic groups (Northern Finland, Caribbean, African, Irish, Indian and 'other white'). When analyzed individually, only one SNP out of the total of 57 gave a significant signal in three different cohorts (UK Biobank, Helsinki and Northern Finland). (4) Biological significance: The genes located within the loci associated with leiomyomas can be divided into two groups: genes related to genome integrity and genes commonly altered in cancers (left), and genes related to the development of the genitourinary system and genes involved in hormonal processes (right). (5) Phenotypic associations: The risk score was associated with the number of leiomyomas per patient, with a higher prevalence of leiomyomas in African women, and with the presence of MED12 mutations in the tumors. A SNP located within the TERT gene was associated with shorter telomeres.
In the third phase Välimäki et al. validated their candidates in six different ethnic groups. The genomic risk score was linked to the development of uterine leiomyomas in all six groups, confirming the involvement of these loci in the disease, independent of ethnicity. The researchers also identified an elevated risk in Black Africans compared to Irish (Caucasian), which could explain the differences in the leiomyoma prevalence.
In the fourth phase Välimäki et al. explored the biological significance of the loci they had identified by searching for genes located within these loci. The genes they identified could be classified into two groups: i) genes implicated in preserving the integrity of the genome and genes commonly implicated in cancer (such as TP53, which is sometimes called the 'guardian of the genome', and TERT, which helps to ensure that the ends of chromosomes remain intact during cell divisions); ii) genes related to the development of the genitourinary system and genes involved in hormonal processes, some of which are also deregulated in cancers (such as the gene for the estrogen receptor gene ESR1).
In the fifth phase the researchers showed that the risk score was positively associated with the number of leiomyomas per patient and a higher prevalence of the disease in African women compared to women with Caucasian ancestry. Overall the results are consistent with a recent study, by a different group, that compared cases and controls from the Icelandic population and Caucasians from the UK Biobank (Rafnar et al., 2018). Surprisingly, the results of Välimäki et al. showed that a variant called rs5937008, which is located in chromosome X near the MED12 gene locus, predisposed women to the subtype of leiomyomas in which the MED12 gene is altered. This result suggests that carriers of the rs5937008 variant have an increased risk of developing MED12-mutated leiomyomas in particular.
The study by Aaltonen, Välimäki, Kuisma and co-workers – who are based the University of Helsinki, Helsinki University Hospital, the University of Oulu and the Karolinska Institute – raises questions that are specific to leiomyomas. For example, what mechanisms orchestrate the process between susceptibility and tumorigenesis? There are also more general questions that remain unanswered: why, for example, do benign tumors – which can carry mutations similar to those seen in malignant tumors – remain benign (Crago et al., 2015; Agnihotri et al., 2016)? Answering such questions will benefit both research into leiomyomas and cancer research in general.
References
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Molecular and clinical attributes of uterine leiomyomasTumor Biology 39:101042831771022.https://doi.org/10.1177/1010428317710226
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The direct and indirect costs of uterine fibroid tumors: a systematic review of the literature between 2000 and 2013American Journal of Obstetrics and Gynecology 213:141–160.https://doi.org/10.1016/j.ajog.2015.03.019
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Epidemiology of uterine fibroids: a systematic reviewBJOG: An International Journal of Obstetrics and Gynaecology 124:1501–1512.https://doi.org/10.1111/1471-0528.14640
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© 2018, Rivera
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Genome-wide Association Study: Not so benign
eLife 7:e42181.
https://doi.org/10.7554/eLife.42181
Further reading
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- Epidemiology and Global Health
- Genetics and Genomics
Background:
Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations.
Methods:
We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504).
Results:
Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (–0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (–0.043±0.013 kg, p=0.0011) in the combined cohorts.
Conclusions:
This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers.
Funding:
This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.
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- Cancer Biology
- Genetics and Genomics
It takes more than 20 years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here, we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into six modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.
