Motoi Murata

Second cancer after radiation therapy for cancer of the uterine cervix

Radiation‐induced cancers after radiation therapy for cancer of the uterine cervix were investigated on 11,855 patients including 5725 patients treated with radiation therapy alone, 1969 postoperative radiation therapy and 4161 surgery alone. The observed‐to‐expected ratios of the second primary cancer was 0.933 for the patients with radiation therapy alone and 1.074 for the patients with postoperative radiation therapy, respectively. No significant increase was observed in the risk of second primary cancers when all sites were combined. However, assessing on site by site basis, significant excess was noted for the rectum cancer, leukemia, and bladder cancer for the radiation therapy group but not for the surgery group. A significant excess of lung cancer was observed in both radiation therapy and surgery groups, which was attributed to some other causative factors. Radiation‐induced cancers were suggested to develop apparently in organs involved in the irradiated field.

Population cytogenetics of rare fragile sites in Japan

SummaryA population cytogenetic study of three groups of rare fragile sites defined in Human Gene Mapping 8 (HGM8, Berger et al. 1985) has been conducted using peripheral blood lymphocytes of healthy Japanese subjects. We have examined 1,022 blood donors for folate-sensitive and bromodeoxyuridine (BrdU)-requiring, and 845 for distamycin A-inducible fragile sites. Out of 17 rare autosomal fragile sites defined in HGM8, the following six were identified in Japan; folate-sensitive fra(2)(q11), fra(11)(q13) and fra(11)(q23), distamycin A-inducible fra(16)(q22) and fra(17)(p12), and BrdU-requiring fra(10)(q25). The incidences of distamycin A-inducible fra(16)(q22) (1.42%) and fra(17)(p12) (3.08%) were considerably higher than those of the other sites in Japan. Furthermore, a folate-sensitive fra(17)(p12) and a distamycin A-inducible fra(8)(q24.1) have been newly found in the present study. Their incidences were 0.10% (1/1,022) and 0.71% (6/845), respectively. Since the expression of this fra(17)(p12) was induced by fluorodeoxyuridine, supressed by thymidine, but not induced by distamycin A, it can be classified as a folate-sensitive site. The expression of the new distamycin A-inducible fra(8)(q24.1) was also enhanced by treatment with Hoechst 33258, berenil and 4′,6-diamidino-2-phenylindole (DAPI). This fragile site fulfils all four classical criteria suggested by Sutherland (1979) and also new criteria for a rare fragile site defined in HGM8 (Berger et al. 1985).

The changing sex ratio in Japan.

SummaryThe simultaneous effects of maternal age and birth order on the secondary sex ratio have been examined using data on about 59 million births which occurred in Japan during the period from 1947 to 1978 except 1950. Non-linear negative association between the sex ratio and birth order was observed.The secondary sex ratio in Japan has been increasing during the period of 1900 through 1978. The change in birth order distribution can explain only a part of the increase in the sex ratio. The decrease in stillbirth rate was not only negatively correlated with the increase in the sex ratio at birth but also with that in fetal deaths. Therefore, it seems that there are some unexplainable factors associated with the increase in the secondary sex ratio other than the decrease in the stillbirth rate. The present results strongly suggest that the true cause of the secular trend in the secondary sex ratio in Japan will be found in the very early stage of pregnancy or at the time of conception.

A new rare distamycin a-inducible fragile site, fra(11)(p15.1), found in two acute nonlymphocytic leukemia (ANLL) patients with t(7;11)(p15-p13;p15)

SummaryFragile sites were analyzed in normal peripheral lymphocytes from two acute nonlymphocytic leukemia patients with t(7;11)(p15-p13;p15) leukemic cells. To induce expression of fragile sites, cultures were exposed to folate deprivation (M-F10), BrdU, distamycin A, or Hoechst 33258. Fragility at 11p15.1 was induced by distamycin A and Hoechst 33258 but was not seen in M-F10, BrdU, and control cultures. Fra(11)(p15.1) was found neither in healthy Japanese subjects (0 in 845) nor in patients with leukemia or other hematologic disorders without the t(7;11) (0 in 126). From these results, fra(11)(p15.1) can now be calssified as a rare distamycin A-inducible fragile site. Furthermore, this fra(11)(p15.1) coincided with one of the breakpoints of the t(7;11)(p15-p13;p15).

The secondary sex ratio paternal age maternal age and birth order in Japan

The simultaneous effects of several variables on the secondary sex ratio have been examined using data from over 3.7 million births which occurred in Japan during 1975--6. A weak and negative association between sex ratio and birth order was observed but it was not significant in the statistical sense. A negative effect of paternal age--birth order interaction was obtained when maternal age was controlled. The quadratic model is much more powerful than the linear model in explaining the sex ratio variability.

An analysis of the age distribution of colon cancer in adenomatosis coli.

For the purpose of elucidating the genetic and environmental interaction in human carcinogenesis, the age distribution of colon cancer in adenomatosis coli (AC) patients in Japan and England were investigated and compared. According to the multiple mutation theory of carcinogenesis, the rate of tumor production is presented by a natural logarithm of the reciprocal of the survival fraction (the proportion on diagnosed colon cancer by age t either among AC patients or total colon cancer cases), and thus is given by a power function of t. The number of hits necessary for colon cancer development in AC patients was estimated to be 4.2 or 4.4 for males and 3.4 or 3.3 for females in Japanese cases, whereas it was 4.7 or 3.9 and 3.6 or 3.2, respectively, in English cases. The estimates are compatible between countries. On the other hand, from the age specific prevalence curve, number of hits in general population was estimated to be 5.0 for both sexes in Japan, which is approximately one hit less than the values for English general population, at least in males. The present results, when taking into account the geographic and/or chronologic variations in colon cancer frequency, suggest that the etiology of colon cancer in younger patients is primarily determined by a genetic predisposition whilst environmental factors are much more influential for the development of colon cancer in older patients.

Nature of Distamycin A-Inducible Fragile Sites

Five rare distamycin A-inducible fragile sites have been identified on human chromosomes: fra(8)(q24.1), fra(11)(p15.1), fra(16)(p12.1), fra(16)(q22), and fra(17)(p12). All of these fragile sites are located at the junction of Giemsa-positive (G) and negative (R) bands and their expression can be induced by a variety of AT specific DNA ligands. Analysis of family data indicate that the distamycin A-inducible fragile sites segregate as a simple codominant trait with complete penetrance, and probands receive these fragile site genes equally from mothers and fathers. Based on current knowledge of chromosome instability, the nature of distamycin A-inducible fragile sites is discussed. Distamycin A-inducible fragile sites appear to be unique chromosomal regions particularly susceptible to fragility under certain stress conditions. They may also be hot spots for recombination, gene amplification, and integration of foreign genomes.

Distamycin A-inducible fragile sites and cancer proneness

To determine the baseline frequency of autosomal rare fragile sites in cancer patients, we conducted a population cytogenetic study of 370 patients with leukemias, solid tumors, and other neoplastic disorders. Twenty carriers of rare fragile sites were detected in this patient group. The rare autosomal fragile sites were at fra(8)(q24), fra(11)(p15), fra(16)(p12.1), fra(16)(q22), and fra(17)(p12). All of these fragile sites were found to be distamycin A inducible. Compared with a population incidence in healthy subjects (44 of 845, 5.21%), the overall incidence of distamycin A-inducible fragile sites was not higher in the patient group (20 of 370, 5.41%). Analysis of these individual fragile sites and particular diseases, however, suggests that the distamycin A-inducible fragile sites may play a role in the etiology of leukemia, myeloproliferative disorders, and benign tumors.

Heritable fragile sites and cancer: fra(16)(q22) in lymphocytes of an acute nonlymphocytic leukemia patient with inv(16)(p13q22).

Fragile site testing was performed on normal peripheral blood lymphocytes from three acute nonlymphocytic leukemia patients who carried inv(16)(p13q22) in malignant cells. Cultures were treated with BrdU, distamycin A, Hoechst 33258, or folic acid deprivation to induce fragile site expression. One patient was found to be a carrier of fra(16)(q22), but the expression was observed only by Hoechst 33258 treatment.

Identification of the human ERK gene as a putative receptor tyrosine kinase and its chromosomal localization to 1p36.1: A comparative mapping of human, mouse, and rat chromosomes

From a newly determined cDNA sequence of the human ERK gene, a highly hydrophobic portion was identified upstream of the putative tyrosine kinase domain. This is the first evidence that the ERK protein possesses a receptor-like membrane-spanning structure. Fluorescence in situ hybridization analysis of R-banded metaphase chromosomes revealed that the ERK gene is located in chromosome region 1p36.1. This locus is near the frequent translocation breakpoint or deletion region of neuroblastoma and some other cancers. A comparative mapping study of the mouse and rat homologues indicated that each counterpart maps to the mouse chromosome 4D2.2-D3 and rat chromosome 5q36.13 regions, both of which have conserved linkage homology to human chromosome 1p.