Frequent microsatellite instability in lung cancer from chromate‐exposed workers

Abstract

Although chromium has been the most extensively investigated metal with respect to mutagenicity and carcinogenicity, its genetic effects in humans are only partly understood. Our previous study demonstrated that lung cancer from chromate-exposed workers infrequently (20%) displayed p53 gene mutations as well as a particular mutation pattern. In the present study, we examined the replication error (RER) and loss of heterozygosity (LOH) in 38 lung cancers from 28 chromate-exposed workers (chromate lung cancer group) and in 26 lung cancer patients without chromate exposure (non-chromate lung cancer group), using six microsatellite markers containing CA repeats: D3S647 (3p23), D3S966 (3p21.3), D3S1289 (3p21.1), D5S346 (5q21-q22), D9S161 (9p21), and TP53 (17p13.1). The RER phenotype was defined as the presence of microsatellite instability (MSI) at two or more loci. Thirty (78.9%) of 38 tumors in the chromate lung cancer group exhibited RER. In contrast, only four (15.4%) of 26 tumors in the non-chromate lung cancer group exhibited RER. The frequency of RER in the chromate lung cancer group was significantly higher than that in the non-chromate lung cancer group (P < 0.0001). By contrast, the frequency of LOH at 3p, 5q, 9p, and 17p loci in tumors with chromate exposure was not significantly different from that in tumors without chromate exposure. In the chromate lung cancer group, the period of chromate exposure in workers with RER (24.5 +/- 6.7 yr) was significantly longer than that in workers without RER (17.0 +/- 3.5 yr) (P = 0.0046). In addition, a longer period of chromate exposure was associated with a tendency toward a higher frequency of MSI. This finding suggests that MSI may play a role in chromium-induced carcinogenesis. In addition to our previous study of p53 mutations, the present findings suggest that the carcinogenic mechanism of chromate lung cancer may differ from that of non-chromate lung cancer.

Microscopic analysis of chromium accumulation in the bronchi and lung of chromate workers

“…27,28 There was no significant difference in loss of heterozygosity (LOH) at 3p between chromate-induced lung carcinomas and non-chromate-induced lung carcinomas. 13 In contrast, the frequency of RER in chromate-induced lung carcinomas (78.9%) was significantly higher than in non-chromate-induced lung carcinoma (15.4%). 13 Sozzi et al 29 reported that MSI was found not only in lung carcinoma (32%) but also in normal epithelia (36%).…”

“…13 In contrast, the frequency of RER in chromate-induced lung carcinomas (78.9%) was significantly higher than in non-chromate-induced lung carcinoma (15.4%). 13 Sozzi et al 29 reported that MSI was found not only in lung carcinoma (32%) but also in normal epithelia (36%). Wistuba et al 30 reported a progressive increase in LOH frequency according to increasing severity of histopathologic changes in squamous cell carcinoma.…”

“…31,32 A previous study performed by our group demonstrated that 9 of 10 early squamous cell carcinomas of the proximal bronchi exhibited MSI in chromate workers with lung carcinoma. 13 Currently, we are evaluating MSI, LOH, and methylation of the p16 gene in these specimens (an early malignancy, dysplasia, squamous metaplasia, and normal epithelia) with chromate exposure. Clarification of the correlation between genetic aberrations and chromium accumulation in these specimens will aid in elucidating the mechanism of carcinogenesis in chromiuminduced lung carcinoma.…”

“…In a previous study, Hirose et al 13 evaluated microsatellite instability (MSI) in 38 lung tissue specimens from 31 chromate-exposed workers. In the current study, the distribution of chromium was measured in bronchial and lung tissue specimens from 10 of 31 chromate-exposed workers with lung carcinoma (Table 1).…”

“…A previous study reported the replication error-positive (RERϩ) phenotype of these 10 lung carcinoma tissue specimens from chromate-exposed workers. 13 The RERϩ phenotype was defined as the presence of MSI at two or more loci, referring to the recommendation of the National Cancer Institute. 14 Informed consent was obtained from all patients before sample collection, in accordance with institutional guidelines.…”