Quantifying substantial carcinogenesis of genetic and environmental factors from measurement error in the number of stem cell divisions

Xinhui Liu; Jifeng Yang; Hongkai Li; Qing Wang; Yuanyuan Yu; Xiaoru Sun; Shucheng Si; Lei Hou; Lu Liu; Fan Yang; Ran Yan; Yifan Yu; Zhentao Fu; Zilong Lu; Dejin Li; Hao Xue; Xiaolei Guo; Fuzhong Xue; Xiaokang Ji

doi:10.1186/s12885-022-10219-w

Quantifying substantial carcinogenesis of genetic and environmental factors from measurement error in the number of stem cell divisions

BMC Cancer. 2022 Nov 19;22(1):1194. doi: 10.1186/s12885-022-10219-w.

Authors

Xinhui Liu^#^{1

2}, Jifeng Yang^#³, Hongkai Li^{1

2}, Qing Wang^{1

2}, Yuanyuan Yu^{1

2}, Xiaoru Sun^{1

2}, Shucheng Si^{1

2}, Lei Hou^{1

2}, Lu Liu^{1

2}, Fan Yang^{1

2}, Ran Yan^{1

2}, Yifan Yu^{1

2}, Zhentao Fu⁴, Zilong Lu⁴, Dejin Li⁵, Hao Xue⁶, Xiaolei Guo⁴, Fuzhong Xue^{7

8}, Xiaokang Ji^{9

10}

Affiliations

¹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhuaxi RoadShandong Province, Shandong, 250012, Jinan, China.
² Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
³ Shandong Health Care Industry Association, Jinan, Shandong, 250002, China.
⁴ Shandong Center for Disease Control and Prevention, Jinan, Shandong, 250014, China.
⁵ Shandong Provincial Big Data Center, Jinan, Shandong, 250011, China.
⁶ Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
⁷ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhuaxi RoadShandong Province, Shandong, 250012, Jinan, China. xuefzh@sdu.edu.cn.
⁸ Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. xuefzh@sdu.edu.cn.
⁹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhuaxi RoadShandong Province, Shandong, 250012, Jinan, China. jxk@sdu.edu.cn.
¹⁰ Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. jxk@sdu.edu.cn.

^# Contributed equally.

Abstract

Background: The relative contributions of genetic and environmental factors versus unavoidable stochastic risk factors to the variation in cancer risk among tissues have become a widely-discussed topic. Some claim that the stochastic effects of DNA replication are mainly responsible, others believe that cancer risk is heavily affected by environmental and hereditary factors. Some of these studies made evidence from the correlation analysis between the lifetime number of stem cell divisions within each tissue and tissue-specific lifetime cancer risk. However, they did not consider the measurement error in the estimated number of stem cell divisions, which is caused by the exposure to different levels of genetic and environmental factors. This will obscure the authentic contribution of environmental or inherited factors.

Methods: In this study, we proposed two distinct modeling strategies, which integrate the measurement error model with the prevailing model of carcinogenesis to quantitatively evaluate the contribution of hereditary and environmental factors to cancer development. Then, we applied the proposed strategies to cancer data from 423 registries in 68 different countries (global-wide), 125 registries across China (national-wide of China), and 139 counties in Shandong province (Shandong provincial, China), respectively.

Results: The results suggest that the contribution of genetic and environmental factors is at least 92% to the variation in cancer risk among 17 tissues. Moreover, mutations occurring in progenitor cells and differentiated cells are less likely to be accumulated enough for cancer to occur, and the carcinogenesis is more likely to originate from stem cells. Except for medulloblastoma, the contribution of genetic and environmental factors to the risk of other 16 organ-specific cancers are all more than 60%.

Conclusions: This work provides additional evidence that genetic and environmental factors play leading roles in cancer development. Therefore, the identification of modifiable environmental and hereditary risk factors for each cancer is highly recommended, and primary prevention in early life-course should be the major focus of cancer prevention.

Keywords: Cancer prevention; Environment; Epidemiology; Measurement error; Stem cell division.

MeSH terms

Carcinogenesis / genetics
Cell Self Renewal
Cerebellar Neoplasms*
Humans
Medulloblastoma*
Risk Factors

Abstract

MeSH terms

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