Somatic mutations in the cancer genome and inter-individual variations in
the human genome are critical keys to improving the cancer clinics. The aim
of our division is to find "seeds" that improve the treatment and
prevention of cancer by identifying and elucidating the biological significance
of somatic mutations in cancer genomes and genetic polymorphisms of cancer
patients. We are working together with NCC staff from hospitals, the Research
Center for Cancer Prevention and Screening, and the Center for Cancer Control
and Information Service to fight lung cancer, the most common cause of cancer-related
deaths in Japan and worldwide.
- Genes for personalized therapy
Novel genes rearranged in lung cancer were searched for by conducting
whole RNA sequencing of lung adenocarcinoma tissues supplied from the
National Cancer Center Biobank using high-speed DNA sequencers. We identified
in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and
the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs)
from people from Japan and the United States (1).
The KIF5B-RET fusion leads to aberrant activation of RET kinase and is
considered to be a new driver mutation of LADC because it segregates from
mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase
inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent
growth activity of NIH3T3 cells. Kinase inhibitors are now standard treatment
for patients with lung cancer whose tumors harbor specific mutant kinases,
and the RET fusion protein was considered potentially to be responsive
to existing targeted therapies using RET kinase inhibitors. The development
of assays to assess RET fusions and other driver mutations in each patient
will offer the potential to routinely parse lung cancer into multiple
different clinically relevant molecular disease types in the near future.
A project focusing on this issue has started in collaboration with NCC
staff from hospitals. An investigator-initiated clinical trial to address
the therapeutic efficacy of vandetanib will start in 2013.
Genes involved in DNA repair and/or chromatin remodeling are being analyzed
to improve the efficiency of existing therapeutic methods. Non-homologous
end joining (NHEJ) and homologous recombination (HR) are major repair
pathways for DNA double strand breaks (DSBs) generated by ionizing radiation
and anti-cancer drugs. We established an assay for evaluating NHEJ activity
against DSBs in chromosomal DNA in human cells (2-3).
Using this assay, we revealed that CBP and p300, histone acetyltransferases
(HATs), promote repair by facilitating accumulation of NHEJ proteins (2).
We also revealed that CBP/p300 HATs promote HR (4). Therefore, CBP/p300
HATs are possible target for sensitization of tumors to radio- and chemotherapies.
In fact, garcinol, a natural compound with an inhibitory activity against
CBP/p300 HATs, was identified as a promising radiosensitizer (5). We also
revealed that ACF1, a chromatin remodeling protein, promotes repair by
facilitating accumulation of NHEJ proteins (6).
- Genes for personalized prevention
Genetic factors underlying lung adenocarcinoma risk of Asians are being
searched for to comprehensively understand the molecular mechanism of
lung carcinogenesis (6-7). A genome-wide association study comprising
a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535
controls confirmed two previously reported risk loci, 5p15.33 and 3q28,
and identified two new susceptibility loci, 17q24.3 and 6p21.3 (6).
Another genome-wide association study of 5,510 never-smoking female lung
cancer cases and 4,544 controls, which were drawn from 14 studies from
mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong, identified
three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 x10-18),
6q22.2 (rs9387478, P = 4.14 x 10-10)
and 6p21.32 (rs2395185, P = 9.51x10-9) (7). These data provide evidence
supporting a role for genetic susceptibility in the development of lung
adenocarcinoma in Asians. These results will be basic information to improve
prevention of lung adenocarcinoma through identification of high-risk
individuals for development.
Predictive markers for responses of lung cancer patients to chemotherapy
are being searched for to improve the efficacy of this therapeutic approach.
Single nucleotide polymorphisms (SNPs) of DNA repair genes were examined
in 640 non-small cell lung cancer patients, who received platinum-based
doublet chemotherapy in the National Cancer Center Hospital and whose
responses were evaluated by the Response Evaluation Criteria in Solid
Tumors (RECIST) (8). Through this study, SNPs in the TP53 and PARP1 genes
were indicated to be involved in inter-individual differences in their
response to platinum-based doublet chemotherapy.