In this large prospective cohort, we found that higher serum cysteine concentrations were associated with significantly reduced risk of both OSCC and GCA. Those in the highest quartile of serum cysteine had a 30% lower risk of OSCC and a 40% lower risk of developing GCA relative to those in the lowest quartile. These inverse associations were stronger for those in the older age groups for both cancer sites. Of note, the serum cysteine concentrations reported here (median: 196nmol/mL; IQR: 178–196 nmol/mL) were significantly lower than those reported for healthy/control subjects in the UK (median: 240nmol/L; IQR: 216–262 nmol/L) [24
] and Norway (median: 318 nmol/L; IQR: 289–337 nmol/L) [25
This is the first study to evaluate the relationship between serum cysteine concentration and risk of oesophageal or gastric cancer. Indeed, we could identify just 3 studies that have looked at (plasma) cysteine in the context of malignancies at other sites. Most recently, one study examined the association between cysteine, homocysteine, and cancer risk in 812 invasive breast cancer cases and matched controls [14
]. This group reported a positive association between cysteine and breast cancer risk; those in the highest quintile of plasma cysteine had a relative risk of 1.65 (95% CI: 1.04, 2.61) compared to those in the lowest quintile, and the association was dose-dependent (Ptrend
= 0.04). In contrast, an investigation of 712 incident in situ
and invasive breast cancer cases found that women in the highest quintile of plasma cysteine had a significantly lower risk of breast cancer relative to those in the lowest quintile (RR: 0.44; 95% CI: 0.26, 0.74), and this inverse association was dose-dependent (Ptrend
= 0.002) [15
]. Lastly, a study of 147 women with squamous intraepithelial lesions of the cervix, 185 women with atypical squamous cells of undetermined significance (ASCUS), and 191 women with cytologically normal Pap smears reported that women in the highest quartile of plasma cysteine had a significantly lower risk of ASCUS than those in the lowest quartile (OR: 0.3; 95% CI: 0.2, 0.7) [13
]. Given the large number of biologic pathways which cysteine is known to modulate, either directly or indirectly, it may not be surprising that it has been both positively and inversely associated with cancer risk in previous studies: it’s role in carcinogenesis is likely determined by both tumour type and physiologic context.
While our results suggest some potential for cysteine (or the related N
-acteylcysteine) as a chemopreventive agent, evidence from the few reported animal and human studies is mixed. In a rat model where oesophageal papillomas and squamous cell carcinomas and liver tumours were induced, oral administration of N
-acetylcysteine significantly reduced the multiplicity of oesophageal tumours but had no effect on the incidence or multiplicity of liver tumours [26
]. A second study, using a rat model of oesophageal adenocarcinoma where tumours were induced via oesophagogastroduodenal anastomosis, reported that N
-acetylcysteine alone did not significantly decrease the incidence of oesophageal adenocarcinomas; however N
-acetylcysteine in combination with α-tocopherol produced a significant reduction in tumour incidence [27
]. Further evidence from animal studies suggests that N
-acetylcysteine dose may be critical in determining its effect. In a rat mammary cancer model, a low dose of N
-acetylcysteine modestly decreased, and a high dose significantly increased, tumour occurrence [28
]. The single study that we have identified which related to gastric cancer reported that N
-acetylcysteine inhibited human gastric cancer SJ-89 cell growth by inducing apoptosis and DNA synthesis arrest [29
]. A randomized trial of 2592 former or current smokers with head and neck or lung cancers found no effect on survival or the incidence of second primary tumours following 2 years of N
-acetylcysteine supplementation [30
]. On the other hand, a small study of 7 volunteers found that carcinogenic acetaldehyde produced by smoking cigarettes could be completely inactivated by sucking a tablet containing 5mg of L
], suggesting some potential for cysteine as a chemopreventive agent in certain settings.
Without accurate assessment of dietary intake, it is impossible to tell whether serum cysteine may correlate with general protein intake in the current study population. In another analysis from the same cohort, individuals eating meat more than 12 times a year had a significantly reduced risk of OSCC (relative to those who ate meat less than 4 times a year). Higher egg consumption (>36 times/year, relative to 2 or fewer times/year) was associated with a significantly reduced risk of both OSCC and GCA [31
]. However, it is likely that higher intake of protein (namely meat and eggs) is a proxy for both higher socioeconomic status and higher general nutritional status.
Our study has a number of strengths, including the prospective study design, the large number of cancer cases, the availability of data on potential confounders, a state-of-the-art measurement method for serum cysteine concentrations and the virtually complete follow-up of all study participants.
Our study also has several limitations. As with any study of this kind, unidentified, unmeasured confounders could explain the association we report (for the total model r2
= 0.18). The large size of the study, the precision of the lab analyses, the close follow-up of trial participants, and the rigorous documentation of cancer diagnoses suggest that neither exposure nor disease misclassification are likely to have significantly influenced our estimates. There is always a concern that pre-clinical disease could lead to alterations in serum measurements, thus creating a misleading association, but we found no difference in the exposure-disease associations between those with cancers diagnosed within the first 2 years of the study and those diagnosed after 2 years. Cysteine participates in a myriad of biological pathways and the specific pathways involved in the risk reduction we observed are not clear. Lastly, the generalisability of our study may be limited, due to the specificities of the population under study (see ). In particular, low protein intake in this population [32
] may be associated with the relatively low range of serum cysteine concentrations which we found.
In this large prospective population study, we found that individuals with higher baseline serum concentrations of cysteine were associated with a significantly reduced risk of both OSCC and GCA. These associations appear biologically plausible. Cysteine should be investigated for it’s potential as a chemopreventive agent for upper gastrointestinal cancers.