Some studies have shown that epidermal growth factor receptor (EGFR) mutations can be heterogeneously distributed in individual tumors. In this study, we re-evaluated the distribution of EGFR ...mutations within tumors.
We used multiple approaches, including an analysis of simultaneous dual hot spot mutations, a trans-sectional analysis of individual lung adenocarcinomas, and comparisons of the mutation patterns between primary and metastatic sites and between primary and recurrent tumors.
None of the 862 tumors harboring an EGFR mutation showed simultaneous dual hot spot mutations, although identical EGFR mutations were found throughout individual tumors in a trans-sectional analysis involving 50 tumors divided into three parts and five lung adenocarcinomas divided into 100 parts. In addition, no discordant mutation patterns were detected among 77 paired primary and metastatic site samples or among 54 primary and recurrent tumor pairs.
All of these results suggest that the heterogeneous distribution of EGFR mutations is extremely rare. However, it is possible that pseudoheterogeneity occurs because of a combination of mutant allele-specific imbalance and heterogeneously distributed EGFR amplification, especially when a less sensitive method is used for detection. Specifically, when EGFR amplification occurs, the mutant allele is amplified, and this amplification is involved in invasive growth. Accordingly, invasive growth area significantly over-represents the mutation signal. In contrast, weak EGFR mutation signals in the area without EGFR amplification may not reach the threshold of detection because of the mixture with normal cells. Such unbalanced mutation signals might lead to pseudoheterogeneity.
Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted ...two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.
Although a growing body of evidence suggests a link between diabetes and cancer, it is not clear whether diabetes independently increases the risk of cancer. We conducted a comprehensive assessment ...of the association between pre‐existing diabetes and total and site‐specific cancer risk based on a pooled analysis of eight cohort studies in Japan (>330 000 subjects). We estimated a summary hazard ratio by pooling study‐specific hazard ratios for total and site‐specific cancer by using a random‐effects model. A statistically increased risk was observed for cancers at specific sites, such as colon (hazard ratio; HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Increased risk was also suggested for other sites, and diabetes mellitus was associated with an overall 20% increased risk in total cancer incidence in the Japanese population. The association between these two diseases has important implications for reiterating the importance of controlling lifestyle factors and may suggest a possible strategy for cancer screening among patients with diabetes. Studies continuously investigating the risk factors for diabetes are also important.
infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with
infection, on the ...risk of gastric cancer has not been widely evaluated.
We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and
infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).
Germline pathogenic variants in nine genes (
,
,
,
,
,
,
,
, and
) were associated with the risk of gastric cancer. We found an interaction between
infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval CI, 2.22 to 29.81; P = 0.02). At 85 years of age, persons with
infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with
(45.5% 95% CI, 20.7 to 62.6 vs. 14.4% 95% CI, 12.2 to 16.6).
infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).
Lung cancers are classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer due to their different treatment and prognosis. Although many studies have reported the specific survival ...of SCLC patients treated at cancer hospitals, survival from population-based data has rarely been reported.
We analyzed survival of SCLC cases diagnosed from 1993 through 2006 from a population-based cancer registry of six prefectures. To assess trends in SCLC survival, we defined three periods that mirrored developments in SCLC treatment: period 1, 1993-1998; period 2, 1999-2001; and period 3, 2002-2006. Assessments were based on relative survival (RS), excess hazard, and conditional survival.
A total of 10,911 SCLC patients were analyzed. Five-year RS among limited disease SCLC (LD-SCLC) in periods 1 to 3 was 16.8%, 21.1%, and 21.4%, respectively. Five-year RS among extensive disease SCLC (ED-SCLC) in periods 1 to 3 was 2.3%, 2.8%, and 2.7%, respectively. Improvement in 5-year RS in periods 2 and 3 compared with period 1 was significant among both LD- and ED-SCLC patients (all P < 0.001). Conditional 5-year RS of LD-SCLC increased from 21% at year 0 to 73% at year 5, while that of ED-SCLC was 3% at year 0 and 53% at year 5.
The prognosis of SCLC patients improved from 1999-2001 but plateaued in 2002-2006, after which no further significant improvement was seen. Continuous survey based on population-based data is helpful in monitoring the impact of developments in treatment.
Recent improvements in 5-year survival of breast cancer have been reported in Japan and other countries. Though the number of long-term breast cancer survivors has been increasing, recent ...improvements in 10-year survival have not been reported. Moreover, the degree of improvement according to age and disease stage remains unclear.
We calculated long-term survival using data on breast cancer diagnosed from 1993 through 2006 from six prefectural population-based cancer registries in Japan. The recent increase in 10-year relative survival was assessed by comparing the results of period analysis in 2002-2006 with the results of cohort analysis in 1993-1997. We also conducted stratified analyses by age group (15-34, 35-49, 50-69, and 70-99 years) and disease stage (localized, regional, and distant).
A total of 63,348 patients were analysed. Ten-year relative survival improved by 2.4% (76.9% vs 79.3%) from 1993 through 2006. By age and stage, 10-year relative survival clearly improved in the age 35-49 years (+2.9%; 78.1% vs 81.0%), 50-69 years (+2.8%; 75.2% vs 78.0%) and regional disease (+3.4%; 64.9% vs 68.3%). In contrast, the degree of improvement was small in the age 15-34 years (+0.1%; 68.2% vs 68.3%), 70-99 years (+1.0%; 87.6% vs 88.6%), localized disease (+1.1%; 92.6% vs 93.7%) and distant metastasis (+0.9%; 13.8% vs 14.7%).
These population-based cancer registry data show that 10-year relative survival improved 2.4% over this period in Japan. By age and stage, improvement in the age 15-34 years and distant metastasis was very small, which suggests the need for new therapeutic strategies in these patients.
Background: Reproductive factors such as age at menarche are known to be associated with disease risk, but data on trends in these factors in Japan are limited. In this study, we investigated secular ...trends in reproductive factors and explored their potential association with socioeconomic and historical events.Methods: We conducted a retrospective analysis of 62,005 Japanese women born between 1890 and 1991 using a survey conducted over 25 years. Trends in reproductive factors were analyzed using linear and joinpoint regression models, and their associations with major historical events involving Japan were evaluated.Results: We found that the age at menarche showed a significant downward trend (P-value<0.001) over the century. Three joinpoints were identified, in 1932 (15.23 years old), 1946 (13.48 years old), and 1959 (12.71 years old), which indicated that average age at menarche decreased by approximately 0.8% per year between 1932 and 1946, and then by 0.4% per year between 1946 and 1959, both of which were statistically significant. However, after 1959, age of menarche remained stable. Analyses of other reproductive factors found significant changes, including a decrease in parity and the number of babies breastfed, and an increase in age at first birth.Conclusion: Age at menarche showed a long-term downward trend in Japan, with significant change points in annual percent change. Other factors showed secular changes in trends as well. These change points were observed at the same time as historical events, namely wars and economic development, suggesting that socioeconomic and environmental changes at the population level affect reproductive factors in females.
The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of ...a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer‐predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer‐free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. We identified 309 pathogenic variants among 4,850 variants in the 27 cancer‐predisposing genes. Pathogenic variants in the following four cancer‐predisposing genes were associated with a high risk of lymphoma: ATM (odds ratio OR, 2.63; 95% confidence interval CI, 1.25–5.51; p = 1.06 × 10−2), BRCA1 (OR, 5.88; 95% CI, 2.65–13.02; p = 1.27 × 10−5), BRCA2 (OR, 2.94; 95% CI, 1.60–5.42; p = 5.25 × 10−4), and TP53 (OR, 5.22; 95% CI, 1.43–19.02; p = 1.23 × 10−2). The proportion of carriers of these genes was 1.6% of lymphoma patients. Furthermore, pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma (OR, 21.57; 95% CI, 7.59–61.26; p = 8.07 × 10−9). These results provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment, such as other neoplasms.
We found that pathogenic variants in the four cancer‐predisposing genes (ATM, BRCA1, BRCA2, and TP53) were associated with lymphoma risk. Pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma. These results would provide novel insights concerning monogenic form into lymphoma classification.
PDF
