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. 2024 Jan 4;27(7):550–558. doi: 10.1007/s12603-023-1947-4

Famine Exposure during Early Life and Risk of Cancer in Adulthood: A Systematic Review and Meta-Analysis

J Zhou 1, Y Dai 2, Z Zuo 1, Ting Liu 3, Suyi Li 1
PMCID: PMC12929998  PMID: 37498102

Abstract

Objectives

Emerging evidences have explored the association between famine exposure during early life and cancer risk in adulthood, but the results remain controversial and inconsistent. This study aimed to provide a comprehensive evidence on the relation of famine exposure to later cancer risk.

Design

Systematic review and meta-analysis.

Methods

Relevant reports published up to March, 2022 were identified by searching PubMed, Embase, Web of sciences and Medline databases. Pooled relative ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the effect famine exposure on cancer risk.

Results

Totally, 18 published articles with 6,061,147 subjects were included in this study. Compared with unexposed group, early life famine exposure dramatically increased the risk of cancer in adulthood (RR=1.13, 95% CI: 1.04–1.22). The pooled RRs were different in terms of sex, exposure severity, exposure period, famine type, study design type and cancer location. A remarkably elevated risk for cancer was discerned in women exposed to famine (RR=1.09, 95% CI: 1.00–1.18), severe exposure (RR=1.12, 95% CI: 1.02–1.22) and adolescence exposure (RR=1.76, 95% CI: 1.02–2.50), Chinese famine exposure (RR=1.55, 95% CI: 1.29–1.82) and cohort studies (RR=1.28, 95% CI: 1.13–1.42). Moreover, a significant association of early-life famine exposure with increased risk of breast (RR=1.16, 95% CI: 1.05–1.27) and stomach cancers (RR=1.89, 95% CI: 1.24–2.54) was observed.

Conclusion

This meta-analysis suggests that exposure to famine during early life may increase the risk of cancer in adulthood. The above-mentioned association is pronounced in women exposed to famine, severe exposure, adolescence exposure, Chinese famine, cohort studies, breast and stomach cancers. It is essential for decision-makers to take targeted measures for improving population awareness regarding the long-term effect of early life nutritional status.

Key words: Famine exposure, early life, cancer, systematic review, meta-analysis

Introduction

The worldwide burden of cancer morbidity and mortality is increasing rapidly (1). As leading cause of death worldwide after cardiovascular disease, the number of new cancer cases reached 19.3 million globally, and nearly 10 million (nearly one in six) people died from cancer in 2020 (2). The global of cancer is predicted to be 28.4 million cases in 2040, a 47% rise from 2020 (3), which will have generated great challenges to global public health. The burden of cancer has grown over time owing to the complicated reasons, including aging and burgeoning population, and alternations in the prevalence of related risk factors (4, 5). Recently, factors related to early-life energy balance have been reported to have long-term effects on risk of cancer (6).

Famine stages could be deemed as natural experiments that may furnish unique insights to assess the impact of early life undernutrition on adverse health outcomes in adulthood (7, 8). It has been assumed that malnutrition during early life could elicit an adaptive response to increase survival in a sparse nutritional condition (9). While individuals subsequently experienced adequate nutrition or overnutrition, enhancing susceptibility to the development of chronic metabolic diseases in adulthood (10). And compelling evidence suggested that early life suffered from famine exposure is associated with obesity, T2DM, hypertension, and metabolic syndrome in adulthood (8, 11, 12, 13, 14), of these are risk factors for cancer (15, 16, 17, 18). Therefore, a possible link between famine exposure during early life and an increased risk for cancer in adulthood was supposed.

Moreover, several plausible biological mechanisms, such as epigenetic modifications and post-traumatic stress disorder (PTSD), have been proposed to explain the relation between famine exposure and cancer risk (19, 20, 21). Epigenetic modifications are reported to be linked with DNA methylation, histone variants and other quantifiable post-translation alternations in the chromatin and RNA, which may enhance the risk of certain chronic diseases including cancer (19, 20). Increasing evidence showed that PTSD may have altered the risk related with famine exposure (21). A series of studies suggested that PTSD was associated with elevated prevalence of smoking and substance abuse (22, 23), which may augment the risk of cancer. Furthermore, PTSD may exert a vital role in cancer via increasing the prevalence of metabolic syndrome, ischemic heart disease and suicide (24, 25, 26). Besides, hunger during early life to bad hygienic conditions and various infectious agents could, at least in theory, also lead to an elevated risk of cancer (27).

However, the consistent view about famine exposure and elevated risk for cancer has not completely been established to date. Given the data limitation, we executed a systematic review and meta-analysis to provide a comprehensive evaluation about the relationship between early life exposure to famine and the risk of cancer in adulthood.

Materials and methods

The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were referred to performing this meta-analysis (Supplementary Table 1), and the protocols were registered on the PROSPERO registry for systematic reviews (CRD: 42022318943). The process of literature search, study selection, and data extraction were carried out by two authors (J.Z. and T.L.) independently. Discrepancies or disagreements between the two authors were resolved by team discussion and consensus.

Table 1.

Characteristics of studies for famine exposure included in the meta-analysis

Author Year Sex Age Continent Study design Exposure severity Exposure period Cancer type Famine type Adjustment for confounding Study quality score
Painter RC et al (32) 2006 475 Women 58–59 (58) European (Netherlands) Cohort NA Fetal Breast cancer Dutch famine Unadjusted ****
Elias SG et al 1 (33) 2004 2341 Women 41–73 (56) European (Netherlands) Case-cohort Moderate, severe Childhood, adolescence, adult Breast cancer Dutch famine Adjusted *******
Hughes LA et al (34) 2010 Men and women (120 852) 56–66 (61) European (Netherlands) Case-cohort Moderate, severe NA Colorectal cancer Dutch famine Adjusted *****
Dirx MJ et al 1 (35) 1999 4417 Women 57–66 (61) European (Netherlands) Case-cohort Moderate, severe NA Breast cancer Dutch famine Adjusted ******
Elands RJJ et al (36) 2019 5726 Women 57–65 (61) European (Netherlands) Case-cohort Moderate, severe NA Breast cancer Dutch famine Adjusted *****
Meng R et al (37) 2020 35938 Men and 56346 women 39–51 (46) Asia (China) Cohort NA Fetal All cancers Chinese Famine Adjusted ******
Jenniskens JCA et al (38) 2022 Men and women (120 852) 55–69 (61) European (Netherlands) Case-cohort Moderate, severe NA Colorectal cancer Dutch famine Adjusted *******
Zhang X et al (39) 2021 80786 Men and 20309 women 30–71(52) Asia (China) Cohort NA Fetal, childhood, adolescence All cancers Chinese Famine Adjusted ******
He D et al (40) 2017 59060 Women 43–55 (50) Asia (China) Cohort NA Fetal, childhood Breast cancer Chinese Famine Adjusted ******
Li QD et al (41) 2012 Men and women (5242278) NA Asia (China) Cohort NA NA Stomach cancer Chinese Famine Adjusted ****
Brand MP et al (42) 2016 7906 Women 50–70 (60) European (Netherlands) Cohort Moderate, severe Childhood, adolescence, adult Colorectal cancer Dutch famine Adjusted ******
Ekamper P et al (43) 2015 41096 Men 63 European (Netherlands) Cohort NA Fetal All cancers Dutch famine Adjusted *****
van Abeelen AF et al (44) 2012 1125 Women and 1129 men NA European (Netherlands) Cohort NA Fetal All cancers, breast cancer Dutch famine Adjusted *******
Elias SG et al 2 (45) 2005 2338 Women 41–73 (56) European (Netherlands) Case-cohort Moderate, severe NA All cancers Dutch famine Adjusted ******
Alimujiang A et al (46) 2016 16469 Women 40–63 (51) Asia (China) Cohort NA NA Breast cancer Chinese Famine Adjusted *****
Schouten LJ et al (47) 2011 62573 women 55–69 (NA) European (Netherlands) Case-cohort Moderate, severe NA Ovarian cancer Dutch famine Adjusted *******
Dirx MJ et al 2 (48) 2003 62573 Women and 58279 men 55–69 (NA) European (Netherlands) Case-cohort Moderate, severe NA Ovarian cancer Dutch famine Adjusted ******
Dirx MJ et al 3 (49) 2001 58279 Men 55–69 (NA) European (Netherlands) Case-cohort Moderate, severe NA Prostate cancer Dutch famine Adjusted ******
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NA: not available.

Search strategy

We searched the databases of PubMed, Embase, Web of Science and Medline up to March 2022 for literature that investigated the relation between early life exposed to famine and the risk of cancer in adulthood. The PICO (Population, Intervention/exposure, Comparison, Outcome/event) framework was opted to identify the eligibility of studies (Supplementary Table 2). The main keywords were retrieved as follows: “famine OR starvation OR hunger OR undernutrition OR malnutrition” AND “cancer OR tumour OR carcinoma OR nubble OR knurl OR lump”. In addition, the potential references of included articles were also filtrated.

Inclusion and exclusion criteria

Initially, articles were screened on the basis of titles and abstracts. Then second screening was relied on the full texts, which were assessed against the following inclusion criteria: (1) an observational study published as an original study; (2) exposure of interest was famine (early life exposed to famine was defined in the original article); (3) outcome of interest was cancer; (4) enough data were available to perform the analyses (i.e., raw binary data or pre-calculated odds ratio (OR), risk ratio (RR), hazard ratio (HR)); (5) nonoverlapping datasets. Exclusion criteria were as follows: (1) reviews, letters, abstracts or conference proceedings; (2) studies using animal models or cell lines; (3) no available data or no adequate data; (4) irrelevant studies.

Data extraction

From studies meeting the inclusion criteria, the following data were extracted: the first author' name, publication year, sex and mean age of participants, location where the study was carried out, study design type, exposure severity, exposure period, cancer type, famine type and adjustment for covariate. Tabular information was extracted from each study by two authors independently (J.Z. and T.L.). Discrepant data were then resolved through consensus.

Quality assessment

The quality assessment was carried out independently by two investigators (J.Z. and T.L.) adopting the Newcastle-Ottawa scale (NOS) (28). The quality of each characteristic was scored ‘low risk' or ‘high risk' based on predefined criteria (29).

Statistical analysis

Firstly, the extracted raw data (RR, OR, or HR) were used to calculate the pooled RRs with their corresponding 95% CI to evaluate the relation between famine exposure and risk of cancer. Non-exposure to famine was considered as a reference group. HR could be directly regarded as RR, and OR could be transformed into RR according to the formula RR=OR/[(1-P0)+(P0*OR)], in which P0 was the incidence of outcome of interest in the nonexposed to famine group (30). Cochran's Q Chi-square test and I2 values were adopted to assess the heterogeneity across studies. The I2 values of 25% or less, near 50%, and near 75% or greater were deemed as low, moderate, and high degrees of heterogeneity, respectively (31). If I2 value was more than 50%, the random effects model (DerSimonian-Liard) was opted as the pooled method. Otherwise, the fixed effects model was adopted. Subgroup analysis was performed in terms of sex of participants, exposure severity, exposure stage, famine type and study design type. Further stratified analysis was evaluated to the impact of famine exposure on different cancer locations. Sensitivity analysis was used to assess whether the single study had a substantial effect on the pooled results. In order to probe the source of heterogeneity, meta-regression analysis was conducted. Publication bias was assessed by visual inspection of funnel plot, Begger's test or Egger's test. Statistical analyses of all data were completed with STATA (version 12.0; Stata Corp, College Station, TX) software. All tests were two-sided, and a P-value <0.05 indicated statistically significant outcomes.

Result

Literature search

The study selection process is displayed in Supplementary Figure 1. Overall, 284 records were identified in the database search (55 from PubMed, 53 from Embase, 116 from Web of sciences and 60 from Medline). Originally, 31 records were excluded due to the duplicated publications. By screening the titles and abstracts, 253 studies were retrieved and reviewed for further assessment, among which 9 records only including abstract, 27 records including animal experiments; 59 records including reviews, editorials, letters; 23 records were found to be not relevant to the current study; and other 16 records including twin studies. One hundred and one articles were subsequently excluded after reviewing the full text, of which 6 studies with unclear exposure, 9 studies without getting the full text, 53 studies were unable to extract data or to transform into available format depended on the published data, 8 studies in one study of the same cohort and other 25 studies with no interesting outcome. Eventually, 18 articles were included in the current meta-analysis.

Study characteristics

The characteristics of the included studies are shown in Table 1. In this meta-analysis, we identified 18 published papers with 6,061,147 subjects, including 9 cohort and 9 case-cohort studies. These papers were published between 1999 and 2022, mostly published from 2009 onwards. With regard to study region, 13 studies were conducted in European, and other 5 studies in Asia. Ten reported studies were classified into moderate and severe exposure based on famine severity. Besides, 6 studies provided data about fetal exposure, 4 studies supplied with childhood exposure, 3 studies reported with adolescence exposure and 2 studies provided with adult exposure. Cancer location was reported in breast (7 studies), in colorectum (3 studies), in stomach (1 study), in ovary (2 studies) and in prostate (1 study). Famine type consisted of Dutch famine (13 studies) and Chinese famine (5 studies). The researchers in 17 studies had adjusted the potential confounding factors when assessed the association between famine exposure and risk of cancer. With respect to the literature quality evaluation, 12 studies were judged at a low risk of bias (Elias SG et al, Dirx MJ et al 1, Meng R et al, Jenniskens JCA et al, Zhang X et al, He D et al, Brand MP et al, Abeelen AF et al, Elias SG et al, Schouten LJ et al, Dirx MJ et al 2 and Dirx MJ et al 3) (33, 35, 37–40, 42, 44–45, 47–49), and 6 at high risk (Painter RC et al, Hughes LA et al, Elands RJJ et al, Li QD et al, Ekamper P et al and Alimujiang A et al) (32, 34, 36, 41, 43, 46).

Early life famine exposure and risk of cancer

Forty-five data from 18 articles evaluated the association between early life famine exposure and the risk of cancer. Among the 18 studies, 29 data exhibited a positive association, while the other 16 data showed no direct relation. The pooled results indicated a significantly positive association between famine exposure during early life and the occurrence risk of overall cancer in adulthood (RR=1.13, 95% CI:1.04–1.22). However, heterogeneity between the studies was strong (I2=84.3%, P <0.001) (Figure 1). Sensitivity analysis revealed that the pooled RR was not substantially influenced by the individual studies, suggesting our stable result in the pooled analysis (Supplementary Figure 2).

Figure 1.

Figure 1

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The forest plot of association between famine exposure and risk of all cancer

Subgroup analyses of associations between famine exposure and cancer

In order to explore the source of heterogeneity, the subgroup analysis was performed based on sex of participants, exposure severity, exposure stage, famine type and study design type. By stratification the sex of participant, we discovered that cancer risk in the only women (RR=1.09, 95% CI: 1.00–1.18) and combined men and women (RR=1.46, 95% CI: 1.11–1.82) exposed to famine was dramatically higher than that in those non-exposed to famine (Figure 2A). However, the association was not observed in only men exposed to famine (Figure 2A). And compared with non-exposed to famine, the severe exposure had a higher risk for cancer (RR=1.12, 95% CI: 1.02–1.22) (Figure 2B). While the moderate exposure showed a non-significantly positive correlation with cancer risk (RR=1.03, 95% CI: 0.92–1.13) (Figure 2B). In stratified analysis by exposure stage, we discerned that fetal (RR=1.01, 95% CI: 0.95–1.07), childhood (RR=1.29, 95% CI: 0.96–1.62), adolescence (RR=1.76, 95% CI: 1.02–2.50), and adult (RR=1.10, 95% CI: 0.83–1.37) famine exposures were associated with increased risk of cancer (Figure 2C). Notably, the correlation was markbly in adolescence exposed to famine (Figure 2C). When we stratified studies by famine type, the summarized result indicated that early life experiencing Chinese famine was significantly associated with elevated risk of cancer in adulthood (RR=1.55, 95% CI: 1.29–1.82) (Figure 2D). But the increased risk was not found in Dutch famine (RR=1.00, 95% CI: 0.94–1.05) (Figure 2D). By subgroup analysis of study design type, we found that famine exposure in cohort studies were dramatically related with an enhanced risk of cancer (RR=1.28, 95% CI: 1.13–1.42) (Figure 2E).

Figure 2A.

Figure 2A

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The forest plot of associations between famine exposure and all cancer stratified by sex

Figure 2B.

Figure 2B

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The forest plot of associations between famine exposure and all cancer stratified by exposure severity

Figure 2C.

Figure 2C

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The forest plot of associations between famine exposure and all cancer stratified by exposure period

Figure 2D.

Figure 2D

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The forest plot of associations between famine exposure and all cancer stratified by exposure period

Figure 2E.

Figure 2E

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The forest plot of associations between famine exposure and all cancer stratified by study type

Further stratified analysis the effect of famine exposure on vary kinds of cancer locations

In the included studies, breast cancer was recorded in 14 data, colorectal cancer in 7 data, stomach cancer in 2 data, ovarian cancer in 4 data, and prostate cancer in 2 data. In terms of cancer location, we observed that famine exposure during early life was linked with elevated risk of breast (RR=1.24, 95% CI: 1.18–1.30), stomach (RR=1.89, 95% CI: 1.24–2.54) and prostate (RR=1.20, 95% CI: 0.98–1.41) cancers (Figure 4). And the significant relationship was noticed in breast and stomach cancers (Figure 3). In contrast to aforementioned cancer types, the pooled analysis displayed that famine exposure during early life was non-significantly related with reduced risk of colorectal (RR=0.90, 95% CI: 0.80–1.00) and ovarian (RR=0.90, 94% CI: 0.72–1.07) cancers (Figure 3).

Figure 3.

Figure 3

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The forest plot of associations between famine exposure and cancer stratified by cancer location

Meta-regression

To explore the sources of heterogeneity, meta-regression analysis was performed by sex of participant, exposure severity, exposure period, famine type, study type and cancer location (Table 2). The adjusted R2 and P value of exposure period, famine type, and study type covariates were 22.80%, 43.78%, 12.60% and 0.029, <0.001, 0.009, respectively.#

Table 2.

Meta-regression of association between famine exposure and risk of cancer

Covariates β SE T P values 95% CI Tau2 Adjusted R2 (%)
Sex 0.071 0.055 1.29 0.204 −0.04, 0.18 0.061 3.67
Exposure severity 0.104 0.072 1.45 0.156 −0.04, 0.25 0.019 1.17
Exposure period 0.123 0.054 2.29 0.029 0.01, 0.23 0.056 22.80
Famine type 0.398 0.085 4.69 <0.001 0.23, 0.57 0.038 43.78
Study type −0.235 0.086 −2.74 0.009 −0.41, −0.06 0.059 12.60
Cancer location −0.041 0.035 −1.16 0.256 −0.11, 0.03 0.035 0.78
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Adjusted R2 (%), the current covariate can explain the size of heterogeneity; β, regression coefficient; Tau2, study between the component of variation size.

Publication bias

Publication bias was assessed by funnel plots of the standard difference in means versus the SE, Egger's test or Begger's test. The results suggested no existence of publication bias in all studies (all P>0.05) (Supplementary Figure 3) (Supplementary Table 3).

Discussion

To the best of our knowledge, this is the first meta-analysis to assess the association between famine exposure during early life and risk of cancer in adulthood. According to our current pooled results, famine exposure may contribute significantly to later cancer risk, particularly in women exposed to famine, severe exposure, adolescence exposure, Chinese famine and cohort study. Further stratified analysis for cancer location demonstrated that early life exposed to famine was obviously associated with increased risk of breast and stomach cancers in adulthood. Therefore, pregnant women and young children should be provided with special care regarding food and nutrition.

Between-study heterogeneity is common in many meta-analysis studies (50, 51), and it is crucial to identity the potential sources of heterogeneity. Thus, we performed subgroup analysis to explore the source of the between-study heterogeneity. When we stratified studies by sex, the pooled RRs were significantly increased in only women and combined men and women exposed to famine. Epidemiological study revealed that women exposed to famine could result in the change of estrogen-receptor (ER) and progesterone-receptor (PR) status (46), which could increase the risk of cancer (52). In subgroup analysis of exposure severity, we observed that severe famine exposure was substantially related with increased risk of cancer. Individual was severely struck by the famine exposure that resulted in low birthweight, nutrient deficiency and undernutrition, which was found to be positively associated with the incidence of some cancers (53). In terms of famine periods, we found that fetal, childhood, adolescence and adult exposures were correlated with elevated risk of cancer, whereas a statistical significance was only noticed in adolescence stage, as indicated in previous study (42). The included number of studies may be reasonable explanation. By subgroup analysis of famine location, we discovered that great Chinese famine exposure during early life was markedly associated with the incremental risk of cancer. In Holland, a period of acute starvation principally influenced a western urban population, whereas, in China, a stage of protracted starvation mainly influenced its huge poor rural population (54). As such, the influence caused by Chinese famine may be more severe and long-lasting than that by Dutch famine, consistent with our subgroup analysis result for famine severity. In addition, by subgroup analysis of study type, the increased risk for cancer was noticed in cohort studies, but not in case-cohort studies. The latter one may increase the bias because the parent cohort is selected much earlier than when the subcohort is selected, and the exposure information is collected at different time points, leading to the underestimated effect (55, 56, 57).

Interestingly, further stratified studies by cancer location, we found that famine exposure during early life was related with elevated risk of breast and stomach cancers. Numerous studies showed that levels of sex steroids and circulating insulinlike growth factor-I are increased in postmenopausal women who were severely exposed to hunger before age 20 years (58, 59). High levels of insulin-like growth factor-I and sex steroids may increase the risk of breast cancer in some reports (60, 61). Moreover, nutritional deficiency predisposes to H. pylori infection (62), which could play a critical role in the development of noncardia gastric cancer (63, 64).

To further investigate the source of heterogeneity, metaregression analysis was carried out in sex of participant, exposure severity, exposure period, famine type, study type and cancer location. The result indicated that exposure period, famine type and study type could explain the heterogeneity source of 22.80%, 43.78% and 12.76%, respectively. The aforementioned reasonable explanation were that adolescence exposure, Chinese famine and cohort studies were significantly associated with increased risk for cancer, as exhibited in our subgroup analysis.

As a pooled analysis of published articles, our study has several advantages. First, these results might facilitate our understanding for cancer and can be employed as a starting point for future study in this field. Second, our pooled analysis enlarged sample size compared with original individual study, thereby increasing statistical power to provide more precise and reliable results. Third, in subgroup analysis stratified by sex of participant, exposure severity, exposure stage, famine location and study type, the pooled RRs for women exposed to famine, severe famine, adolescence exposure, Chinese famine and cohort studies significantly identified the impact of early life famine exposure on cancer. Fourth, most included studies had adjusted for potential confounding factors, decreasing the effects of confounding factors.

However, the current meta-analysis also has caveats that need to be considered when interpreting the pooled findings. First, the adjusted confounders in the included studies were inconsistent, which might result in exaggerating the risk. Second, cancer is not a single disease but multiple conditions, and the mechanistic pathways that may lead to the development of cancer may be diverse. The current pooled analysis were only based on observational studies (case-cohort and cohort) to evaluate the association between malnutrition during early life and cancer risk in adulthood. The relationship assessed in observational studies can be influenced by a large number of factors. As such, well-designed and population-based prospective studies are need to provide more accurate risk estimates after nutritional disturbances during early life. Finally, the potential mechanism underlying famine exposure in risk of cancer is needed to be further probed through animal experiments in the future.

Conclusion

In summary, this study implies that famine exposure during early life may increase the risk of cancer in adulthood. The association is significantly strengthened in women exposed to famine, severe exposure, adolescence exposure, Chinese famine, cohort studies and cancer located at breast and stomach. Our study further supports that early life nutrition has an important effect on health outcome in adulthood. Consequently, individuals exposed to famine for prolonged periods appear, especially those exposed at an early life, to be at increased risk of cancer and should be monitored and screened accordingly.

Acknowledgments

We thank all participants and teaching staff from Anhui Provincial Cancer Hospital for their assistance and support.

Contributor Information

Ting Liu, Email: liuting9019@163.com.

Suyi Li, Email: njlisuyi@sina.com.

Electronic supplementary material

Supplementary material is available for this article at https://doi.org/10.1007/s12603-023-1947-4 and is accessible for authorized users.

Supplementary material, approximately 161 KB.

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Funding sources This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Declaration of interest: The authors have no relevant interests to declare.

Ethical standard: This article does not contain any studies with human participants or animals performed by any of the authors.

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