|
 |
Project : Atomic
Bomb Survivors' Medical Care and Epidemiology |
|
| |
Purpose
The increased incidence of malignancy such as leukemia and solid
tumor are well documented among A-bomb survivors. However, although
it is a main concern for us working in Hiroshima and Nagasaki to
evaluate the molecular mechanism during radiation-induced carcinogenesis,
so far, the epidemiological analysis on molecular alterations with
cancer tissues from A-bomb survivors has not been fully established.
This study aimed to epidemiologically analyze the incidence of oncogenetic
mutations in malignancies from A-bomb survivors in compared with
those from others and detect specific molecules associated with tumorigenesis
in A-bomb survivors.
Members
| Ichiro Sekine* |
Professor, Department of Molecular
Pathology |
| Yasushi Miyazaki |
Assistant Professor, Department of Internal
Medicine of Atomic Bomb Disease, Nagasaki University Hospital |
| Masahiro Nakashima |
Assistant Professor, Tissue and Histopathology
Section |
| Hisayoshi Kondo |
Assistant Professor, Biostatics Section |
*Responsible scientist.
All belong to Atomic Bomb Disease Institute, Nagasaki University
Graduate School of Biomedical Sciences except for Yasushi Miyazaki.
Plans
- Hematopoietic oncology
(1) Molecular epidemiology of leukemias
Several types of leukemia, of which incidence rose among
the atomic bomb survivors, showed the highest incidence
in 5 to 10 years after atomic bomb exposure. It is suggested
that radiation-induced genetic changes had important roles
in the pathogenesis of these leukemias. Fusion of two genes
is a frequent genetic change so far found among de novo
leukemia caused by the translocation of chromosomes; the
fusion of bcr and abl genes is found in almost all cases
of chronic myeloid leukemia (CML), 30% of adult acute lymphoid
leukemia (ALL) and 5% of childhood ALL, and the fusion
of tel and abl gene can be detected in about a quarter
of childhood ALL cases. However, we do not know the frequencies
of these fusion-type genetic changes of leukemias seen
among atomic bomb survivors. In this project, we are aiming
to show whether the same “fusion type” genetic
changes exist in leukemias (CML and ALL) of the atomic
bomb survivors, so that to reveal the characteristics of
radiation-induced leukemias. DNA and RNA of leukemias among
the atomic bomb survivors are available from several sources;
paraffin blocks of pathological specimens, formaldehyde
treated organ samples, and bone marrow and peripheral blood
smear samples. We will extract nucleic acids from those
samples that are suitable for the detection of fusion genes
seen among sporadic leukemias and compare the incidence
of those genetic changes between de novo and radiation-induced
leukemias. We are also planning to apply fluorescent in
situ hybridization (FISH) method to those analyses.
(2) Epidemiology of myelodysplastic syndromes among atomic
bomb survivors
Myelodysplastic syndrome (MDS) is a disorder of hematopoietic
stem cells showing ineffective hematopoiesis resulting
in various degree of cytopenia. The number of patients
with MDS seems to increase along with the extension of
life span, but the relationship between MDS and radiation
exposure has not been analyzed fully. Our preliminary data
suggests that the incidence of MDS related inversely to
the distance from hypocenter among the atomic bomb survivors
in Nagasaki. MDS is seen mainly in the elderly, and it
is possible that the effect of radiation still remains
to increase the incidence of MDS even more than 50 years
after the explosion of atomic bomb. We will take an epidemiological
approach to test our preliminary findings.
- Solid tumors
A series of clinical information about 111 751 of the Nagasaki
A-bomb survivors registered as a data base at the Atomic
Bomb Disease Institute, Nagasaki University School of
Medicine. On the other hand, there are 29 647 A-bomb
survivors who have been pathologically diagnosed as neoplasms
including both benign and malignant tumors by Nagasaki
Tumor Registries since 1973. To epidemiologically analyze
the relation between the incidence of solid tumor/multiple
cancer and A-bomb radiation, we are now linking the pathological
diagnosis to clinical information of each A-bomb survivor
and establishing a data base about neoplastic lesions
from A-bomb survivors. Our pilot study has already shown
a high correlation between distance from the hypocenter
and incidence of thyroid cancers, breast cancers, skin
cancers, and meningiomas. Thus the study focuses on these
four tumors and multiple cancers. Although the relation
between A-bomb radiation and some solid tumors among
A-bomb survivors has been suggested, oncogenetic abnormalities
in these tumors are not fully evaluated. We are planning
to examine ret/PTC rearrangements in thyroid cancers,
amplification of c-myc and HER-2 genes in breast cancers,
and loss of 6q, 9p, 10q, 14q and gain of 17q in meningiomas
by FISH with archival tissue samples, and epidemiologically
clarify the molecular abnormalities in cancers from A-bomb
survivors.
|
Activities
- Solid tumors
We have recently investigated the incidence of several
tumors among Nagasaki A-bomb survivors from 1973 through
2000 in relation to the distance from the hypocenter.
The analysis showed a high correlation (p<0.001) between
distance from the hypocenter and incidence of thyroid
cancers, breast cancers, skin cancers, and meningiomas.
Thus, the epidemiological analysis of oncogenetic abnormalities
in these tumors should be important to gain an insight
into tumorigenesis among A-bomb survivors. Resected tumors
from A-bomb survivors have been preserved as formalin-fixed
paraffin-embedded tissues. It is so hard to extract enough
quality and amount of DNA/RNA from pathological materials
stored for many years. To effectively use these valuable
materials, we have just started to make tissue microarray
of cancers from A-bomb survivors and analyze aberrant
oncogenes with fluorescence in situ hybridization (FISH).
FISH analysis with paraffin-embedded sections of archival
breast cancer tissue blocks demonstrated HER-2 gene amplification.
Its results were concordant with immunohistochemical
results. Furthermore, ret/PTC rearrangements were also
detected in a case of 10 paraffin-embedded papillary
thyroid cancers from A-bomb survivors by FISH. FISH with
tissue microarray should be a useful technique to analyze
aberrant genes with numerous archival materials from
A-bomb survivors.
|
|
|
