The association between dietary intakes of methionine, choline and betaine and breast cancer risk: A systematic review and meta-analysis

Female breast cancer is the most frequently diagnosed malignancy worldwide and a leading cause of cancer mortality among women in many countries. According to the estimates of the GLOBCAN project of 2020, female breast cancer accounts for 24.5 % of all cancer cases and for 15.5 % of all cancer deaths in women [1] . Age-standardised incidence rates vary considerably across regions, almost four-fold from 95.5/100,000 in Australia and New Zealand to 26.6/100,000 in South Central Asia. These variances reflect differences in the presence of key risk factors for breast cancer between countries and regions [12] . Nutritional status and dietary factors are of particular interest among those risk factors because they are considered potentially important modifiable risk factors. Development, progression, and/or recurrence of breast cancer may be affected by nutrients, such as folate, methionine, choline, and betaine trough their impact on the DNA [3] . Hence, these nutrients play a key role within the one-carbon metabolism, a cyclical cellular process that provides methyl-groups in the form of S-adenosylmethionine (SAM) [4] . SAM is the universal methyl-group donor responsible for all biological methylation reactions, including DNA methylation [5] . Any deficiency or excess in the intake of these nutrients related to one-carbon metabolism may influence the bioavailability of SAM, and thereby could affect the DNA methylation process. Aberrant DNA methylation patterns may lead to modifications in gene expression and genome instability, resulting in an altered disease risk [46] .

Folate intake or blood folate levels, as a one-carbon metabolism related nutrient, has been studied extensively in relation to breast cancer risk, resulting in several meta-analyses of observational studies 7891011121314 . In contrast to the ample amount of folate studies, there is less literature available on methionine, choline, and betaine. Currently, the epidemiological studies assessing the association between dietary consumption of methionine and breast cancer risk, generate conflicting results [15] . Furthermore, the increasing amount and quality of food consumption databases for choline and betaine in the recent years provide now the opportunity to estimate their association with breast cancer risk, however reporting conflicting findings [1617] .

Considering the inconsistent evidence provided by previous studies, the aim of this systematic review and meta-analysis is to summarise and evaluate the existing evidence from observational studies on the association between dietary intake and blood concentrations of choline, betaine, and methionine and the risk of breast cancer. Given the availability of several recently published meta-analyses on the association between dietary folate intake, total folate intake or circulating folate levels and breast cancer risk, only a systematic search was conducted for folate. A better understanding of these associations will contribute to the totality of available scientific evidence that may substantiating the development of appropriate public health messages and primary prevention strategies, e.g., by setting future recommendations for dietary intakes to reduce breast cancer incidence in the long run.