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ORIGINAL ARTICLE
Ahead of print publication  

Racial/ancestral diversity in 174 toxicity-related radiogenomic studies: A systematic review


 Department of Diagnostic Imaging and Radiotherapy, Faculty of Health Sciences, The National University of Malaysia, Kuala Lumpur, Malaysia

Date of Submission27-Dec-2018
Date of Decision23-May-2019
Date of Acceptance09-Jun-2019
Date of Web Publication06-Feb-2020

Correspondence Address:
Noorazrul Yahya,
Faculty of Health Sciences, The National University of Malaysia, Jalan Raja Muda Aziz 50300, Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_896_18

 > Abstract 


Purpose: This study systematically reviews the distribution of racial/ancestral features and their inclusion as covariates in genetic–toxicity association studies following radiation therapy.
Materials and Methods: Original research studies associating genetic features and normal tissue complications following radiation therapy were identified from PubMed. The distribution of radiogenomic studies was determined by mining the statement of country of origin and racial/ancestrial distribution and the inclusion in analyses. Descriptive analyses were performed to determine the distribution of studies across races/ancestries, countries, and continents and the inclusion in analyses.
Results: Among 174 studies, only 23 with a population of more one race/ancestry which were predominantly conducted in the United States. Across the continents, most studies were performed in Europe (77 studies averaging at 30.6 patients/million population [pt/mil]), North America (46 studies, 20.8 pt/mil), Asia (46 studies, 2.4 pt/mil), South America (3 studies, 0.4 pt/mil), Oceania (2 studies, 2.1 pt/mil), and none from Africa. All 23 studies with more than one race/ancestry considered race/ancestry as a covariate, and three studies showed race/ancestry to be significantly associated with endpoints.
Conclusion: Most toxicity-related radiogenomic studies involved a single race/ancestry. Individual Participant Data meta-analyses or multinational studies need to be encouraged.

Keywords: Ethnicity, radiation therapy, radiogenomic, radiotoxicity



How to cite this URL:
Zuber SH, Yahya N. Racial/ancestral diversity in 174 toxicity-related radiogenomic studies: A systematic review. J Can Res Ther [Epub ahead of print] [cited 2020 May 25]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=277830




 > Introduction Top


Radiation therapy is one of the most vital modalities for treating cancer. Radiation therapy can be an excellent treatment option and is currently included, either as a primary therapy or as part of a combination therapy for approximately half of the cancer patients worldwide.[1] However, the therapeutic benefit of radiation therapy is limited by the tolerance of normal tissues to radiation injuries.[2],[3],[4],[5]

Standard radiation therapy schedule is usually recommended for the treatment of cancer patients. This is not optimal as it has been observed that patients are not homogeneous in terms of the reaction of normal tissues to radiation therapy. For some patients, due to different inherent radiosensitivities, the standard radiation therapy is too harmful with regard to the normal tissue toxicity risks which cannot be fully attributed to dose and dose distribution alone.[6],[7] It is suggested that genetics plays an important role in this heterogeneous response to radiation.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21]

Radiogenomic studies aim to establish the associations between genetic variations and the response to radiation therapy.[22],[23],[24] Ultimately, the goal is to produce genetic-based risk models that can stratify patients according to radiosensitivity based on this genetic information. In the last decade, candidate gene association studies have identified several potential genetic predictors for radiosensitivity.[25],[26],[27],[28],[29],[30],[31],[32],[33]

Challenges for radiogenomic studies are numerous including obtaining cohorts of patients with good-quality data on races or ancestries. A factor affecting the risk of radiation therapy-related toxicity is not a true confounder, unless it is also associated with genotype, typically through race/ancestry.[34] Population stratification results in genetic variation in race/ancestry compared to difference due to the association of genes with disease. This is a significant confounder in all genetic association studies, which can make comparisons across studies with different ancestry difficult.[35]

The challenge for radiogenomic studies is to quantify the nongenetic risk factors accurately so that the influence of genetics can be detected reliably.[36],[37] In order to improve the quality of studies, the Radiogenomic Consortium has proposed a list of 18-item checklist – Strengthening the Reporting of Genetic Association studies in Radiogenomics guidelines – to include in the reports of radiogenomic studies.[35] One of the items in the checklist, specifying the race/ancestry details, is the interest of the current study. We aimed to systematically review radiogenomic studies involving radiation therapy-related toxicity to evaluate the distribution of race/ancestry. This study will also determine whether the researchers consider racial/ancestrial factors in the formation of the statistical models and whether the factors are significantly associated with toxicity.


 > Materials and Methods Top


Search strategy

We searched the PubMed database through a comprehensive search strategy including the terms “radiogenomic,” “genome,” “genome wide association,” “toxicity,” and “radiation therapy” based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for reporting systematic reviews and meta-analyses[38] [Supplementary A]. The search result was last updated in November 2017. References from the retrieved articles were also searched for additional publications. Studies related to radiation therapy and radiation toxicity with genetic associations were included. Case reports, meta-analyses, and review articles were excluded. If different publications reported the same sample, we selected the publication with the highest number of samples or that provided the most detailed information. This search was run concurrently with a previous study that has since been published.[37]

Data extraction

Investigators independently extracted data from each included study. Disagreements were resolved by discussion among all investigators. The following data were extracted: first author, year of publication, country of origin, race/ancestry group, and sample size. The statement of “mixed” ancestry without detailing the composition was not accepted. In studies with more than one race/ancestry, the details were recorded, and the inclusion in the analyses was noted. We extracted the race/ancestry “as is” without assumptions of what constitutes of a race/ancestry due to differences of definition across studies. For example, we maintained “White” and “non-Hispanic White” in two categories.

Data analysis

Data collected were tabulated and descriptively analyzed. We tabulated studies based on country and continents including the number of patients included per million population of the continent.

Ethical statement

This study does not contain any studies with human or animal subjects performed by any of the authors.


 > Results Top


Eligible studies

Initial unrestricted search yielded 784 studies. Title and abstract review done by two independent reviewers resulted in 198 potentially relevant studies. On the basis of full-text review, 24 studies were excluded because they were systematic reviews, meta-analysis, or independent validation (10); endpoints not toxicity (6); duplicates (3); case studies (2); correspondence (1); cell study (1); and full text not retrievable (1). Finally, a total of 174 studies were included in the analysis [Supplementary B]. The literature search flow diagram is depicted in [Figure 1].
Figure 1: Literature search flow diagram

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Distribution of radiogenomic studies across continents

The highest number of studies performed was in Europe, with 77 studies across the region, involving 22,693 patients, which translates to 30.6 patients/million (pt/mil) [Table 1]. Forty-six studies were conducted in Asia, with 2.4 pt/mil; 46 studies in North America, with 20.8 pt/mil; 3 studies in South America, with 0.361 pt/mil; and 2 studies in Oceania, with 2.1 pt/mil involved. No study was performed in Africa.
Table 1: Number of patients recruited in toxicity-related radiogenomic studies across continents

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Distribution of radiogenomic studies across countries

For countries with three and more studies, tabulation data were recorded with the inclusion of number of patients involved [Table 2]. A total of 14 countries had more than two studies and 43 studies were recorded for the United States involving 7160 patients with several race populations (African-American, White, Asian, Hispanic, non-Hispanic White, Spanish, European-American, European, and others). Based on the results, other countries had an average number of studies between 3 and 28 and less variation in races/ancestries.
Table 2: Number of patients for countries with ≥3 studies

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Race/ancestry reporting and inclusion in analyses

Among the 174 studies, there were only 23 studies with more than one race/ancestry variation [Table 3]. Studies performed in the United States often include ancestry variations as a variable compared to other countries. The most common populations include Caucasian and African-American. All the 23 studies considered race/ancestry as Z covariate, and three studies showed race/ancestry to be a significant factor for the endpoints studied.
Table 3: Characteristics of studies with participants from more than one race/ancestry

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 > Discussion Top


Radiosensitivity has been shown to be related to race/ancestry in some studies.[39],[40],[41] There are suggestions that these differences in radiosensitivity are due to the differences of inherited polygenic trait between races/ancestries.[41],[42] Thus, the information on race/ancestry is expected to be reported in radiogenomic studies and preferably the genetic ancestry needs to be accounted in the analyses.[43]

From our systematic review, we found that studies are mostly homogenous in terms of the race/ancestry of accrued patients. This is advantageous in terms of assessing the genetic predictors for a specific race/ancestry without the confounding impact of genetic ancestrial diversity. However, it is increasingly acknowledged that single-nucleotide polymorphisms (SNPs) reported to be an important indicator for a phenotype in one race/ancestry may not be consistent with other race/ancestry populations, which may account for differences in individual disease susceptibility.[41],[44],[45],[46] For example, although associations between the transforming growth factor-1 (TGF-1) T869C polymorphism and development of chronic obstructive pulmonary disease have been demonstrated in Western countries, no such associations were observed in the Korean and Chinese populations. In addition, both the T869C and G915C SNPs have been shown to contribute to hepatic fibrosis susceptibility in White patients, but no such associations were observed in the Chinese population.[47],[48],[49],[50] Thus, the utilization of genetic associations derived using data extrapolated from patients of one race/ancestry requires further validation in the target population.[45]

Studies were predominantly performed in North America and Europe, accruing mostly individuals from European ancestry. Because majority of the studies were conducted in Caucasian populations and allelic frequencies vary between ethnic groups, little is known regarding the association between genetic variants and postradiation therapy toxicities. Underrepresentation of cohorts from Africa, South America, and, to a lesser extent, Asia and Oceania was found. This is rather expected given higher concentration of low- and middle-income countries in these continents. The lack of knowledge on specific genes important for treatment individualization may increase the gap of cancer treatment outcome between countries, which is already high due to differences in the accessibility to radiation therapy facilities.[51],[52],[53]

Studies in the United States are mostly racially heterogeneous, with 21/23 studies accruing more than one race/ancestry came from the country. This may be associated to the racial diversity in the country with no difference in accruals in clinical trials based on race.[54] Accruals of ethnic minorities including Blacks, Hispanics, and Asians in toxicity-related radiogenomic studies may help us better understand the impact of genetic ancestry diversity toward specific gene–toxicity associations. This may mitigate the lack of studies from South America and Africa.

It is understandable that radiogenomic studies are inherently expensive, and it is not prudent and economical to expect more studies from financially deprived countries. Thus, a method to allow the inclusion of ancestrally diverse small studies into a data pool may be preferable. The Radiogenomic Consortium, which aims to foster international collaborative research projects in radiogenomics through sharing of biospecimens and data, may be a good place to start for this initiative.[55] The sharing of data may allow Individual Patient Data meta-analysis to be performed. Andreassen et al., in 2016,[56] managed to perform Individual Patient Data meta-analysis for 5456 patients from 17 different cohorts. Unfortunately, the database consists of predominantly cancer patients from European ancestry.

Detailed information on the process leading to participant inclusion in a study, especially on the identification of ancestry of each individual, is important because participants might come from different racial/ancestral cohorts from the target cohorts to which any findings will be applied to.[35] Detailed reporting of these elements may not be viewed with importance and thus, may contribute to incomplete reporting. The suboptimal reporting of race/ancestry details may be due to the perception that the clinical features including radiation dose parameters and procedures are more interesting, and studies focus on the clinical aspects rather than the overall views on genetic pools within different races/ancestries.[57] Moving forward, as suggested by Kerns et al., the transparency and completeness of radiogenomic study requires greater standardization of study designs, data collection, and data analysis, which can only be achieved by adopting a common set of guidelines for reporting radiogenomics studies, which include race/ancestry details.[35],[58] The findings in this field of research may not benefit other racial groups if the research is performed primarily with individuals of certain racial/ancestral background.[41]

Studies have demonstrated that racial differences represent important risk factors for normal tissue injury from radiation therapy and should be considered in future studies.[9],[39],[40],[41] Different genetic backgrounds between races/ancestries may explain contradictory results in various studies. For example, Wang et al., 2015, compared the allele frequencies and genotype distributions of TGF-1 variants between two analyzed cohorts of White and Chinese populations. In the Chinese cohort, the minor allelic frequency was significantly different from those of Whites. Although it is difficult to separate the effects of ancestry from those of environment, the results suggest that the frequency patterns of polymorphisms in TGF-1 gene vary greatly among different racial groups.[50] However, in our systematic review, only 3 out of the 23 studies which accrued more than one race/ancestry found race/ancestry to be significant. This may be related to the small number of samples when genetic information is considered due to the high cost associated to gene sequencing.


 > Conclusion Top


It is essential to account for race/ancestry to distinguish unexplained toxicity due to race-/ancestry-specific genetic differences. Individual Participant Data meta-analyses or multinational studies need to be encouraged.

Acknowledgment

We thank Xin-Jane Chua for her assistance. We acknowledge funding from the National University of Malaysia (GGPM-2017-095). The funder had no role in the preparation of the article.

Financial support and sponsorship

This study was funded by the National University of Malaysia (GGPM-2017-095). The funder had no role in the preparation of the article.

Conflicts of interest

There are no conflicts of interest.

Supplementary A: Search terms

((((radiogenomics [All Fields] OR (“genome” [MeSH Terms] OR “genome” [All Fields])) OR ((“genome” [MeSH Terms] OR “genome” [All Fields]) AND wide[All Fields] AND (“association” [MeSH Terms] OR “association” [All Fields] OR “associations” [All Fields]))) OR (“genetics” [Subheading] OR “genetics” [All Fields] OR “genetics” [MeSH Terms])) AND (“toxicity” [Subheading] OR “toxicity” [All Fields])) AND (“radiotherapy” [Subheading] OR “radiotherapy” [All Fields] OR “radiotherapy” [MeSH Terms])





 
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  [Table 1], [Table 2], [Table 3]



 

 
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