Gregory J. Kirkner
Brigham and Women's Hospital
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Featured researches published by Gregory J. Kirkner.
Gut | 2009
Shuji Ogino; Katsuhiko Nosho; Gregory J. Kirkner; Takako Kawasaki; Jeffrey A. Meyerhardt; Massimo Loda; Edward Giovannucci; Charles S. Fuchs
Background: The CpG island methylator phenotype (CIMP), characterised by widespread promoter methylation, is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on prognosis remains uncertain. Methods: Utilising 649 colon cancers (stage I–IV) in two independent cohort studies, we quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) as well as CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN by using MethyLight technology. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features. Results: After adjustment for other predictors of patient survival, patients with CIMP-high cancers (126 (19%) tumours with ⩾6/8 methylated CIMP-specific promoters) experienced a significantly low colon cancer-specific mortality (multivariate HR 0.44, 95% confidence interval (CI) 0.22 to 0.88), whereas the BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI 1.13 to 3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumours (multivariate HR 0.70, 95% CI 0.36 to 1.37). In stratified analyses, CIMP-high tumours were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to prognostic significance. Conclusion: CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.
Gut | 2006
Shuji Ogino; Mami Cantor; Takako Kawasaki; Mohan Brahmandam; Gregory J. Kirkner; Daniel J. Weisenberger; Mihaela Campan; Peter W. Laird; Massimo Loda; Charles S. Fuchs
Background: The concept of CpG island methylator phenotype (CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation. Aim: To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation. Materials and methods: We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts. Results: There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having ⩾4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, p<10−5) and non-CIMP MSS tumours (6.6%, p<10−4), respectively). Conclusion: CIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.
Journal of the National Cancer Institute | 2008
Shuji Ogino; Katsuhiko Nosho; Gregory J. Kirkner; Takako Kawasaki; Andrew T. Chan; Eva S. Schernhammer; Edward Giovannucci; Charles S. Fuchs
Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer-specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; P(trend) < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; P(trend) = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients.
Journal of Clinical Oncology | 2009
Shuji Ogino; Katsuhiko Nosho; Gregory J. Kirkner; Kaori Shima; Natsumi Irahara; Shoko Kure; Andrew T. Chan; Jeffrey A. Engelman; Peter Kraft; Lewis C. Cantley; Edward Giovannucci; Charles S. Fuchs
PURPOSE PIK3CA mutation and subsequent activation of the AKT pathway play an important role in colorectal carcinogenesis. However, little is known about the prognostic role of PIK3CA mutation in colon cancer. PATIENTS AND METHODS Using 450 resectable colon cancers (stage I to III) in two independent prospective cohorts, we detected PIK3CA mutation in 82 tumors (18%) by pyrosequencing. Cox proportional hazards models were used to calculate hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including the CpG island methylation phenotype, microsatellite instability (MSI), LINE-1 hypomethylation, and p53, CIMP, KRAS and BRAF mutation. RESULTS Compared with patients with PIK3CA wild-type tumors, those with PIK3CA-mutated tumors experienced an increase in colon cancer-specific mortality according to univariate analysis (HR = 1.64; 95% CI, 0.95 to 2.86), which persisted after adjusting for other known or potential risk factors for cancer recurrence (including MSI; multivariate HR = 2.23; 95% CI, 1.21 to 4.11). The effect of PIK3CA mutation on cancer survival seemed to differ according to KRAS mutational status. Among patients with KRAS wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in colon cancer-specific mortality (HR = 3.80; 95% CI, 1.56 to 9.27). In contrast, PIK3CA mutation conferred no significant effect on mortality among patients with KRAS-mutated tumors (HR = 1.25; 95% CI, 0.52 to 2.96). CONCLUSION Among patients who undergo a curative resection of colon cancer, PIK3CA mutation is associated with shorter cancer-specific survival. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors.
PLOS ONE | 2008
Katsuhiko Nosho; Natsumi Irahara; Kaori Shima; Shoko Kure; Gregory J. Kirkner; Eva S. Schernhammer; Aditi Hazra; David J. Hunter; John Quackenbush; Donna Spiegelman; Edward Giovannucci; Charles S. Fuchs; Shuji Ogino
Background The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1) as surrogate markers for CIMP-high. However, no study has comprehensively evaluated an expanded set of methylation markers (including these 5 markers) using a large number of tumors, or deciphered the complex clinical and molecular associations with CIMP-high determined by the validated marker panel. Metholodology/Principal Findings DNA methylation at 16 CpG islands [the above 5 plus CDKN2A (p16), CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF) and WRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight). In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), CDKN2A, CRABP1, MINT31, MLH1, p14 and WRN were generally clustered with each other and with MSI and BRAF mutation. KRAS mutation was not clustered with any methylation marker, suggesting its association with a random methylation pattern in CIMP-low tumors. Utilizing the validated CIMP marker panel (including the 5 markers), multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and β-catenin (CTNNB1) activation. Mucinous feature, signet ring cells, and p53-negativity were associated with CIMP-high in only univariate analysis. In stratified analyses, the relations of CIMP-high with poor differentiation, KRAS mutation and LINE-1 hypomethylation significantly differed according to MSI status. Conclusions Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also suggest that KRAS mutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors.
International Journal of Cancer | 2008
Shuji Ogino; Takako Kawasaki; Katsuhiko Nosho; Mutsuko Ohnishi; Yuko Suemoto; Gregory J. Kirkner; Charles S. Fuchs
The CpG island methylator phenotype (CIMP) with widespread promoter CpG island methylation is a phenotype in colorectal cancer, associated with microsatellite instability (MSI) and BRAF mutation. Genome‐wide hypomethylation may also play an important role in genomic instability. However, the relation between global DNA methylation level and methylation in individual CpG islands remains uncertain. Utilizing 869 population‐based colorectal cancers, we measured long interspersed nucleotide element‐1 (LINE‐1) methylation level by Pyrosequencing, which correlates with global DNA methylation level. We quantified DNA methylation in 8 CIMP‐specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) by real‐time PCR (MethyLight technology). LINE‐1 methylation levels in tumors were approximately normally distributed (mean, 61.4%; median, 62.3%; standard deviation, 9.6%). Among the 869 tumors, 128 (15%) were classified as CIMP‐high (≥6/8 methylated promoters). The mean LINE‐1 methylation level was higher in CIMP‐high tumors (65.1%, p < 0.0001) than non‐CIMP‐high tumors (60.7%), and higher in MSI‐high tumors (64.7%, p < 0.0001) than non‐MSI‐high tumors (60.7%). When tumors were stratified by MSI/CIMP status, compared to non‐MSI‐high non‐CIMP‐high tumors (mean LINE‐1 methylation level, 60.4%), the mean LINE‐1 methylation level was higher in MSI‐high CIMP‐high (64.8%, p < 0.0001), MSI‐high non‐CIMP‐high (64.6%, p = 0.03) and non‐MSI‐high CIMP‐high tumors (66.1%, p = 0.0003). In addition, 18q loss of heterozygosity in non‐MSI‐high tumors was correlated with LINE‐1 hypomethylation (p = 0.004). In conclusion, both CIMP‐high and MSI‐high are inversely associated with LINE‐1 hypomethylation, suggesting that CIMP/MSI and genomic hypomethylation may represent different pathways to colorectal cancer. Our data also support a possible link between global hypomethylation and chromosomal instability.
JAMA Internal Medicine | 2009
Jeffrey A. Meyerhardt; Edward Giovannucci; Shuji Ogino; Gregory J. Kirkner; Andrew T. Chan; Walter C. Willett; Charles S. Fuchs
BACKGROUND Although physically active individuals have a lower risk of developing colorectal cancer, few studies have examined whether exercise benefits colorectal cancer survivors. METHODS Derived from the Health Professionals Follow-up Study, we studied colorectal cancer-specific and overall mortality in a cohort of 668 men with a history of stage I to stage III colorectal cancer according to predefined physical activity categories after diagnosis. To minimize bias by occult recurrences, we excluded men who died within 6 months of their postdiagnosis physical activity assessment. RESULTS In a cohort of men with colorectal cancer and no apparent metastases at diagnosis, 50.4% exercised at least 18 metabolic equivalent task (MET) hours per week. Increased physical activity was significantly associated with improved colorectal cancer-specific mortality (P = .002 for trend) and overall mortality (P < .001 for trend). Men who engaged in more than 27 MET hours per week of physical activity had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.47 (95% confidence interval, 0.24-0.92) compared with men who engaged in 3 or less MET hours per week of physical activity. The apparent benefit of physical activity was seen regardless of age, disease stage, body mass index, diagnosis year, tumor location, and prediagnosis physical activity. CONCLUSION In a large cohort of men with a history of nonmetastatic colorectal cancer, more physical activity was associated with a lower risk of colorectal cancer-specific and overall mortality.
Modern Pathology | 2006
Shuji Ogino; Mohan Brahmandam; Mami Cantor; Chungdak Namgyal; Takako Kawasaki; Gregory J. Kirkner; Jeffrey A. Meyerhardt; Massimo Loda; Charles S. Fuchs
Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components (‘the signet group’), 167 carcinomas with various mucinous components (‘the mucinous group’), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (≤19, 20–49, and ≥50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (≥50% signet ring cell tumors) and ≤49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, ≥50% mucinous tumors and ≤49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (≤49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to ≥50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other.
Journal of Clinical Oncology | 2008
Shuji Ogino; Katsuhiko Nosho; Jeffrey A. Meyerhardt; Gregory J. Kirkner; Andrew T. Chan; Takako Kawasaki; Edward Giovannucci; Massimo Loda; Charles S. Fuchs
PURPOSE Energy balance seems to be important in the pathogenesis of colon cancer. Fatty acid synthase (FASN) is physiologically regulated by energy balance and is often upregulated in colorectal cancer. Nonetheless, the influence of FASN expression on patient outcome is uncertain. PATIENTS AND METHODS Using the database of 647 patients with colon cancer in two independent cohort studies, FASN overexpression was detected in 84 tumors (13%) by immunohistochemistry. Cox proportional hazards models calculated hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related tumoral features, including KRAS, BRAF, p53, microsatellite instability and the CpG island methylation phenotype. RESULTS There were 279 deaths, including 160 colon cancer-specific deaths. FASN overexpression was associated with a significant reduction in colon cancer-specific mortality by both univariate and multivariate analyses (adjusted HR, 0.41; 95% CI, 0.19 to 0.89) and an insignificant trend toward improved overall mortality (adjusted HR, 0.75; 95% CI, 0.50 to 1.13). Notably, the effect of FASN expression on mortality might be different according to body mass index (BMI; P(interaction) = .019); the adjusted HR of overall mortality for FASN overexpression was 0.63 (95% CI, 0.39 to 1.02) among patients with BMI less than 27.5 kg/m(2) and 2.91 (95% CI, 1.19 to 7.12) among those with BMI >or= 27.5 kg/m(2). Moreover, the adverse effect of moderate overweight/obesity on overall survival was limited to FASN-positive tumors (adjusted HR, 4.10; 95% CI, 1.14 to 14.8; BMI >or= 27.5 kg/m(2) v < 27.5 kg/m(2)). CONCLUSION Among nonobese patients with colon cancer, tumoral FASN overexpression is associated with improved survival, whereas among moderately overweight or obese patients (BMI >or= 27.5 kg/m(2)), FASN overexpression may predict a worse outcome.
Journal of Clinical Oncology | 2009
Shuji Ogino; Katsuhiko Nosho; Natsumi Irahara; Kaori Shima; Yoshifumi Baba; Gregory J. Kirkner; Jeffrey A. Meyerhardt; Charles S. Fuchs
PURPOSE Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during colon cancer development and is inversely associated with microsatellite instability (MSI). 18q LOH has been reported to predict shorter survival in patients with colorectal cancer, whereas MSI-high status has been associated with superior prognosis. However, it is unclear whether 18q LOH in colorectal cancer has any prognostic implication independent of MSI status and other potential predictors of clinical outcome. PATIENTS AND METHODS Among 555 non-MSI-high colorectal cancers (stage I to IV) in two independent prospective cohort studies, we examined 18q LOH in relation to other molecular events and patient survival. Cox proportional hazard models computed hazard ratio of death, adjusted for clinical and tumoral characteristics, including KRAS, BRAF, PIK3CA, beta-catenin, p53, CpG island methylator phenotype, LINE-1 methylation, and John Cunningham (JC) virus T antigen. RESULTS In multivariate logistic regression, 18q LOH was independently associated with JC virus T antigen (odds ratio [OR] = 1.93; P = .0077), body mass index > or = 30 kg/m(2) (obesity; OR = 2.01; P = .014), high tumor grade (OR = 0.40; P = .018), KRAS mutation (OR = 0.66; P = .40), and LINE-1 hypomethylation (for a 30% decrease; OR = 1.92; P = .045). Five-year colorectal cancer-specific survival was 75% among patients with 18q LOH-positive tumors and 74% among those with 18q LOH-negative tumors (log-rank P = .80). Five-year overall survival was 70% among patients with 18q LOH-positive tumors and 68% among those with 18q LOH-negative tumors (log-rank P = .54). Multivariate analysis did not show prognostic significance of 18q LOH. CONCLUSION In our large prospective study of patients with non-MSI-high colorectal cancer, 18q LOH or allelic imbalance was not associated with patient survival.