Masaru Tsuyuguchi

Microsatellite instability and protein expression of the DNA mismatch repair gene, hMLH1, of lung cancer in chromate-exposed workers

Our previous studies of lung cancer in chromate‐exposed workers (chromate lung cancer) have revealed that the frequency of replication error (RER) in chromate lung cancer is very high. We examined whether the RER phenotype of chromate lung cancer is due to an abnormality of DNA mismatch repair protein. We investigated the expression of a DNA mismatch repair gene, hMLH1, and hMSH2 proteins using immunohistochemistry and microsatellite instability (MSI) in 35 chromate lung cancers and 26 nonchromate lung cancers. Lung cancer without MSI or with MSI at one locus was defined as “RER(−),” lung cancer with MSI at two loci was defined as “RER(+),” and lung cancer with MSI at three or more loci was defined as “RER(++).” The repression rate of hMLH1 and hMSH2 proteins in chromate lung cancer was significantly more than that of nonchromate lung cancer (hMLH1: 56% vs. 20%, P = 0.006, hMSH2: 74% vs. 23%, P < 0.0001). In chromate lung cancer, the repression rate for hMLH1 was 43% in RER(−), 40% in RER(+), and 90% in the RER(++) group. The repression rate of hMLH1 protein in the RER(++) group was significantly higher than that in the RER(−) and RER(+) groups (P = 0.039). The inactivation of hMLH1 expression strongly correlated with the microsatellite high instability phenotype in chromate lung cancer. The genetic instability of chromate lung cancer is due to the repression of hMLH1 protein.

Frequent microsatellite instability in lung cancer from chromate‐exposed workers

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.

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

Background  A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism–jaw tumour syndrome (HPT‐JT).

Familial isolated primary hyperparathyroidism with parathyroid carcinomas : clinical and molecular features

Familial isolated primary hyperparathyroidism (FIHP) is a rare hereditary disorder. We present four patients from a single family with FIHP, and genetic analysis of their parathyroid adenomas and parathyroid carcinoma.

Point Mutations of ras and Gsα Subunit Genes in Thyroid Tumors

We studied 43 thyroid tumors including 5 adenomatous goiters, 7 follicular adenomas, 22 papillary carcinomas, and 9 medullary carcinomas with regard to the presence of point mutations in the genes of Gs alpha subunit (Gsα), Gi2 alpha subunit (Gi2α), H‐ras, K‐ras, and N‐ras by a polymerase chain reaction‐direct sequencing method. An adenomatous goiter and a follicular adenoma showed double mutations at codon 227 and 231, and 4 papillary carcinomas showed mutation at codon 231 of the Gsα gene. An adenomatous goiter, a follicular adenoma, and a papillary carcinoma showed a missense mutation in codon 13 of the K‐ras gene. There were no such missense mutations of these G‐protein or ras genes in medullary carcinomas. These data indicate that the genetic events involved in the oncogenesis of parafollicular C‐cells are different from those of thyroid follicular cells, in which missense mutations of Gsα and ras genes seem to play important roles in tumorigenesis.

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

It is known that chromium is an inhaled carcinogen and an important risk factor in the development of lung carcinoma.

Adult case of accessory cardiac bronchus presenting with bloody sputum.

We report an adult case of accessory cardiac bronchus (ACB) which extended from the carina to the diaphragm. A 32-year-old woman, with a history of frequent respiratory infections since childhood, recently presented with bloody sputum, and was admitted to our hospital. The ACB was detected as a supernumerary bronchus diverging from tracheal bifurcation. Complete resection of the ACB was performed by video-assisted thoracic surgery via minithoracotomy, approaching from the 5th intercostal space. The bloody sputum was caused by chronic inflammation of the ACB. She has been asymptomatic since surgery.

A case of resistance to thyroid hormone diagnosed after total thyroidectomy for thyroid cancer

This is a case of a woman who was diagnosed with resistance to thyroid hormone after total thyroidectomy for thyroid cancer. Preoperative laboratory examination revealed the syndrome of inappropriate secretion of TSH, however, the patient had no thyrotoxic symptoms and no family history. Based on the results of ultrasonography and fine needle aspiration, she was diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. After the surgery, she received L-T4 therapy, but her TSH levels remained elevated. MRI was performed on the brain, but no lesions were found in the pituitary gland. Therefore, she was tested for TRβ gene, and a previously defined mutation, P453S, was detected. Ultimately, she was diagnosed as RTH and treated with L-T4. In this case, the dose of L-T4 needed to be increased to suppress her TSH levels to the normal range or less, and to prevent stimulating malignant cells. Currently, her dose of L-T4 has been increased, and her TSH levels are still lower than normal, however, she has no thyrotoxic symptoms, recurrence or metastasis of thyroid cancer. The patient is currently under careful observation regarding her circulatory and physiological status. In addition, the results of treatment still need to be monitored and evaluated.

610 Mutations of the p53 gene in human lung cancer from chromate-exposed workers

We examined p53 mutations in 20 cancer samples from 19 chromate workers with lung cancer by Polymerase chain reaction-Single strand conformation polymorphism analysis and direct sequencing. Six missense mutations were identified in 4 (20%) of the 20 chromate lung cancer samples. Fewer mutations were found in the patients with lung cancers who had been exposed to chromate than in those who had not. However, the pattern of p53 mutations in lung cancer patients exposed to chromate differed from that of common lung cancers in 3 respects. There were no apparent G to T transversions, which are common base changes in lung cancers. Half of the mutational sites (3/ 6) had changes of AT base-pairs, and 2 of 4 mutational tumor samples had double missense mutations. Our results suggested that chromate exposure may induce point mutation of the p53 gene.

Localized adiposity of the thyroid, clinically mimicking an adenoma

A case of localized adiposity of the thyroid in a 35-year-old woman with a long history of steroid therapy for nephrotic syndrome is reported. A well-demarcated yellowish mass measuring 2 cm in diameter was found in the upper portion of the right lobe of the thyroid. Microscopically, this lesion was composed of mature adipose tissue partially mixed with thyroid tissue and had no distinct capsule. The nontumorous thyroid tissue showed features of Hashimoto’s thyroiditis. At least two factors—hamartomatous malformation and metabolic disturbance-may be involved in the histogenesis of this localized adiposity.