Association Between Copper Excess, Zinc Deficiency, and TP53 Mutations in Esophageal Squamous Cell Carcinoma From Kashmir Valley, India—A High Risk Area

Abstract

Trace element deficiency or excess is implicated in the development or progression in some cancers. Here we report the elevated level of copper and low level of zinc in the plasma of esophageal cancer patients in Kashmir India—a high incidence area. The average level of copper was significantly higher (P < 0.0001) for patients than for controls, with a mean concentration of 169 μg/dl and 149 μg/dl for patients and controls, respectively. The control group consisted of 55 healthy individuals matched for age, sex, and place of residence of the patients. In contrast, the average level of zinc in patients was significantly lower than in controls (P < 0.0001), with a mean concentration of 86.8 μg/dl and 96.1 μg/dl for patients and controls, respectively. The levels of both copper and zinc showed significant differences based on gender and age in patients as compared to controls. Similarly, smokers depicted a significant increase in serum copper (N = 39, P = 0.002) and a decrease in serum zinc approaching level of significance in the patient group as compared to controls. The copper and zinc levels were significantly altered in patients (N = 40) when compared to controls as a function of snuff consumption. The differences in the levels of copper and zinc showed significant association with the consumption of local salted tea up to 1,500 ml per day, but the changes were insignificant beyond that. Patients with poorly differentiated tumors (N = 7) had a higher copper concentration than those with moderately or well-differentiated tumors (P < 0.0001). To validate the general notion that imbalance in copper and zinc levels may lead to higher prevalence of TP53 mutations, we compared the 3 variables, and no association was found between copper concentration and TP53 mutation status; but patients with TP53 mutant tumor had lower zinc levels than those with no mutation. In conclusion, our results point toward a role of the trace element imbalance in the esophageal tumorigenesis in high-risk Kashmiri population exposed to a range of nitroso compounds or their precursors. Further prospective cohort studies are warranted to determine whether change in the plasma zinc and copper homeostasis may represent an independent risk factor for this malignancy as well as a possible target for preventive intervention.

ACKNOWLEDGMENTS

The financial support by Sher-i-Kashmir Institute of Medical Sciences is gratefully acknowledged. We are also very much thankful to Pierre Hainaut, of International Agency for Research on Cancer, Lyon, France, for his valuable suggestions. We also record our thanks to the anonymous reviewers whose valuable comments improved the overall content of the article.

Notes

^a Sex: M = Male, F = Female.

^b Smoking Habit: − = nonsmoker, + = 1–5 cigarettes/day, ++ = 6–10 cigarettes/day, + < eqid 25 > + = 11–15 cigarettes/day.

^c Consumption of snuff: + = Yes, − = No.

^d Salt tea consumed × 100 ml.

^e Site: U = upper one-third, M = middle one-third, L = lower one-third.

^f Grade: PD = poorly differentiated, MD = moderately differentiated, WD = well differentiated.

^a The copper and zinc concentrations are presented as median with interquartile range in parentheses. P values are from t-test between zinc or copper concentration and respective variables like age, sex, smoking habits, snuff, and salt tea consumption.

^b Age and salt tea consumption were available as continuous variable.

^a The copper and zinc concentrations are presented as median with interquartile range in parentheses.

^a The comparisons were made on the bases of age, sex, smoking status, snuff, and salt tea consumption. The P values ≤ 0.05 were considered as significant.