Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah.

BACKGROUND: Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood. AIM: To quantify the risk of CRC in first-degree (FDR), second-degree (SDR) and first cousin (FC) relatives of individuals with CRC, stratified by subsite in the colorectum and age at diagnosis. METHODS: Colorectal cancers diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age and gender-matched CRC-free controls were selected to form the comparison group for determining CRC risk in relatives using Cox regression analysis. RESULTS: Of the 18,208 index patients diagnosed with CRC, 6584 (36.2%) were located in the proximal colon, 5986 (32.9%) in the distal colon and 5638 (31%) in the rectum. The elevated risk of CRC in relatives was similar in analysis stratified for CRC colorectal subsites in the index cases. FDR had similarly elevated risk of all site CRC, whether the index patient had cancer in the proximal colon [hazards ratio (HR): 1.85; 95% CI: 1.70-2.02], distal colon (HR: 1.90; 95% CI: 1.73-2.08) or rectum (HR: 1.83; 95% CI: 1.66-2.02) compared to relatives of controls. This risk was consistently greater for FDR when cases developed CRC below the age of 60 years. CONCLUSIONS: Relatives of CRC patients have a similarly elevated risk of CRC regardless of colonic tumour subsite in the index patient, and it is greatest for relatives of younger age index cases.

Interest and informational preferences regarding genomic testing for modest increases in colorectal cancer risk.

BACKGROUND/AIMS: This study explored the interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. METHODS: Surveys were conducted on 272 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal's Common Sense Model of Self-Regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with interest in SNP testing and preferences for receiving genomic risk communications. RESULTS: Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials (69.5%), oncologists (54.8%), primary-care physicians (58.4%), and the web (58.1%). Overall, persons who were unmarried (p = 0.029), younger (p = 0.003) and with greater cancer-related fear (p = 0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer-related fear was associated with the interest in predictive genomic testing in the intervention group (p = 0.017), but not the control group. CONCLUSIONS: Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups and those with greater cancer fear.

A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer.

PURPOSE: KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. EXPERIMENTAL DESIGN: 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). RESULTS: The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. CONCLUSIONS: The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates.

CA 19-9 and CEA are the most commonly used biomarkers for diagnosis and management of patients with pancreatic cancer. Since the original compendium by Steinberg in 1990, numerous studies have reported the use of CA 19-9 and, to a lesser extent, CEA in the diagnosis of pancreatic cancer. Here we update an evaluation of the accuracy of CA 19-9 and CEA, and, unlike previous reviews, focus on discrimination between malignant and benign disease instead of normal controls. In 57 studies involving 3,285 pancreatic carcinoma cases, the combined sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with benign pancreatic disease the specificity of CA 19-9 was 82.8%. From the combined analysis of studies reporting CEA, the sensitivity was 44.2% (1,324 cases) and the specificity was 84.8% (656 cases). These measurements more appropriately reflect the expected biomarker accuracy in the differential diagnosis of patients with periampullary diseases. We also present a summary of the use of CA 19-9 as a prognostic tool and evaluate CA 19-9 diagnostic and prognostic utility in a 10-year, single institution experience.

The p16(INK4A) tumor suppressor regulates cellular oxidative stress.

Mutations or deletions in the cyclin-dependent kinase inhibitor p16(INK4A) are associated with multiple cancer types, but are more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why the genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following ultraviolet-irradiation and in response to H2O2-induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using small interfering RNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage, which was further enhanced by H2O2 treatment. Elevated ROS levels were also observed in p16-depleted human keratinocytes and in whole skin and dermal fibroblasts from Cdkn2a-deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts was normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by the knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to the potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared with keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why the compromise of p16 predisposes to melanoma over other cancers.

GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance.

Ewing's sarcoma is a malignant bone-associated tumor of children and young adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein. EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the master regulator of Ewing's sarcoma-transformed phenotype. We recently showed that EWS/FLI regulates one of its key targets, NR0B1, through a GGAA-microsatellite in its promoter. Whether other critical EWS/FLI targets are also regulated by GGAA-microsatellites was unknown. In this study, we combined transcriptional analysis, whole genome localization data, and RNA interference knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4 promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation. Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma whose tumors had higher levels of GSTM4 expression had worse outcomes than those with lower expression levels. These data show that GSTM4 contributes to the cancerous behavior of Ewing's sarcoma and define a wider role for GGAA-microsatellites in EWS/FLI function than previously appreciated. These data also suggest a novel therapeutic resistance mechanism, in which the central oncogenic abnormality directly regulates a resistance gene.

Local Excision vs. Radical Resection in T1-2 Rectal Carcinoma: Results of a Study From the Surveillance, Epidemiology, and End Results (SEER) Registry Data.

BACKGROUND: Local excision (LE) has been used in an attempt to preserve anal function in T1-2 rectal carcinoma. The current study compares LE to radical resection (RR), each with or without radiation therapy (RT). METHODS: Patients reported to the SEER registry of the National Cancer Institute from 1988 to 2003 who had T1-2N0M0 rectal carcinoma were identified. A retrospective analysis of survival was performed using the Kaplan-Meier method. Comparative risks of mortality were evaluated using multivariate adjusted Cox regression models. RESULTS: Of 4,320 patients, 13% underwent LE alone, 7% underwent LE plus RT, 70% underwent RR alone, and 10% underwent RR plus RT. On multivariate analysis, patients who underwent LE without RT had inferior overall survival compared to patients who underwent RR (P < .05). Patients who underwent LE with or without RT had inferior cause-specific survival compared to patients who underwent RR (P < .05). CONCLUSIONS: RR without RT was associated with superior overall survival compared to LE without RT, and RR without RT was associated with superior cause-specific survival compared to LE with or without RT. Randomized trials are necessary to determine if LE with or without RT can offer equivalent survival compared to RR in early stage rectal carcinoma.

Variable selection and pattern recognition with gene expression data generated by the microarray technology.

Lack of adequate statistical methods for the analysis of microarray data remains the most critical deterrent to uncovering the true potential of these promising techniques in basic and translational biological studies. The popular practice of drawing important biological conclusions from just one replicate (slide) should be discouraged. In this paper, we discuss some modern trends in statistical analysis of microarray data with a special focus on statistical classification (pattern recognition) and variable selection. In addressing these issues we consider the utility of some distances between random vectors and their nonparametric estimates obtained from gene expression data. Performance of the proposed distances is tested by computer simulations and analysis of gene expression data on two different types of human leukemia. In experimental settings, the error rate is estimated by cross-validation, while a control sample is generated in computer simulation experiments aimed at testing the proposed gene selection procedures and associated classification rules.

Measures of familial aggregation as predictors of breast-cancer risk.

BACKGROUND: Several measures of familial disease aggregation have been proposed, but only a few of these are designed to be implemented at the individual level. We evaluate two of them in the context of breast-cancer incidence. METHODS: A population-based cohort consisting of 114 429 women born between 1874 and 1931 and at risk for breast cancer after 1965 was identified by linking the Utah Population Data Base and the Utah Cancer Registry. Two competing methods were used to obtain predictors of familial aggregation of risk: the number of first-degree relatives with breast cancer (NIST) and the familial standardised incidence ratio (FSIR), which weights the disease status of relatives based on their degree of relatedness with the proband. Relative risks were estimated using Mantel-Haenszel. Poisson regression and spline regression methods. The age-dependent hazard function was also estimated. RESULTS: Compared to a baseline category containing 91.5% of the subjects, the 0.7% of subjects identified as high risk using the FSIR criterion had a relative risk of about 2.8, while those identified as high risk using the NIST criterion had a relative risk of 2.0. Moderate-risk subjects had a relative risk of about 1.75 using either criterion. FSIR was a significant predictor of risk even for those with no affected first-degree relatives. No decline in the baseline risk was observed at advanced ages. CONCLUSIONS: FSIR appears to be a better predictor of breast-cancer risk than NIST, particularly for high-risk subjects.

An alternative stochastic model of generation of oligodendrocytes in cell culture.

According to our previous model, oligodendrocyte--type 2 (O-2A) astrocyte progenitor cells become competent for differentiation in vitro after they complete a certain number of critical mitotic cycles. After attaining the competency to differentiate, progenitor cells divide with fixed probability p in subsequent cycles. The number of critical cycles is random; analysis of data suggests that it varies from zero to two. The present paper presents an alternative model in which there are no critical cycles, and the probability that a progenitor cell will divide again decreases gradually to a plateau value as the number of completed mitotic cycles increases. In particular all progenitor cells have the ability to differentiate from the time of plating. The Kiefer-Wolfowitz procedure is used to fit the new model to experimental data on the clonal growth of purified O-2A progenitor cells obtained from the optic nerves of 7 day old rats. The new model is shown to fit the experimental data well, indicating that it is not possible to determine whether critical cycles exist on the basis of these experimental data. In contrast to the fit of the previous model, which suggested that the addition of thyroid hormone increased the limiting probability of differentiation as the number of mitotic cycles increases, the fit of the new model suggests that the addition of thyroid hormone has almost no effect on the limiting probability of differentiation.

Probability of finding HLA-mismatched related or unrelated marrow or cord blood donors.

Given recent improvements in the technology of transplantation and histocompatibility testing, it is now possible to contemplate using related or unrelated allogeneic hematologic stem cell donors with high degrees of HLA disparity. This paper is a follow-up of an earlier publication on the probability of finding a matched donor (Transplantation 60:778-783, 1995) and addresses the probability of finding a partially mismatched donor. Assuming that a four of six antigen HLA-A, -B, -DR match is acceptable, it is possible to find unrelated donors for patients of any race from a putative registry with fewer than 10,000 potential donors. Further, storing cord blood from newborns in families with a known genetic disease would yield an acceptable future stem cell transplant product in nearly 40% of cases. These results show the potential impact of cord blood donors and emphasize the importance of improvements in transplantation using partially mismatched donors.

Lifestyle and colon cancer: an assessment of factors associated with risk.

Studies of the etiology of colon cancer indicate that it is strongly associated with diet and lifestyle factors. The authors use data from a population-based study conducted in northern California, Utah, and Minnesota in 1991-1995 to determine lifestyle patterns and their association with colon cancer. Data obtained from 1,993 cases and 2,410 controls were grouped by using factor analyses to describe various aspects of lifestyle patterns. The first five lifestyle patterns for both men and women loaded heavily on dietary variables and were labeled: "Western," "moderation," "calcium/low-fat dairy;" "meat and mutagens," and "nibblers, smoking, and coffee." Other important lifestyle patterns that emerged were labeled "body size," "medication and supplementation," "alcohol," and "physical activity." Among both men and women, the lifestyle characterized by high levels of physical activity was the most marked lifestyle associated with colon cancer (odds ratios = 0.42, 95% confidence interval: 0.32, 0.55 and odds ratio = 0.52, 95% confidence interval: 0.39, 0.69, for men and women, respectively) followed by medication and supplementation (odds ratio = 1.68, 95% confidence interval: 1.29, 2.18 and odds ratio = 1.63, 95% CI 1.23, 2.16, respectively). Other lifestyles that were associated with colon cancer were the Western lifestyle, the lifestyle characterized by large body size, and the one characterized by calcium and low-fat dairy. Different lifestyle patterns appear to have age- and tumor site-specific associations.

Identifiability of parameters in the Yakovlev-Polig model of carcinogenesis.

The paper discusses the problem of identifiability for two versions of a two-stage model of carcinogenesis recently introduced by Yakovlev and Polig. In this model, cell killing is allowed to compete with tumor promotion. In the first version of the Yakovlev-Polig model, which is referred to as Model 1, cell killing starts immediately after a carcinogen is administered. In the second version, called Model 2, it is assumed that a cell may be killed only after the process of initiation has been completed. The two versions of the Yakovlev-Polig model suggest explicit formulas for the distribution of time to tumor onset (that is, appearance of the first malignant clonogenic cell) counted from the initial moment of the exposure to a carcinogen. A model of carcinogenesis is identifiable if the set of all model parameters is uniquely determined by the distribution of time to tumor onset. It is shown that, under a natural necessary condition of overlap of supports of the dose-rate function h and the promotion time distributions from a family F, Model 1 is identifiable in the family F for many practically important functions h. In particular, this is the case for a simple model of spontaneous carcinogenesis (h = 1) and for a class of piecewise constant dose-rate functions h with arbitrary family F. Also, this holds for the family of gamma distributions and h supported on an interval and non-vanishing in the interior of this interval. More restrictions need to be imposed on the dose-rate function and the family of promotion time distributions for Model 2 to be identifiable. In particular, for h = 1, Model 2 turns out to be non-identifiable even in the family of gamma distributions.

A stochastic model of temporally regulated generation of oligodendrocytes in cell culture.

The results of our previous analyses suggest that O-2A progenitor cells become competent for differentiation in vitro after they complete a certain number of critical mitotic cycles. The number of critical cycles varies from clone to clone and should be thought of as a random variable. We propose an approach to the analysis of oligodendrocyte generation in vitro based on a stochastic model allowing for an arbitrary distribution of this random variable with a finite support. When applied to experimental data on clonal growth and differentiation of purified O-2A progenitor cells obtained from optic nerves of 1 and 7 day-old rats, the model provides a good quantitative description not only of the first two moments (mean and variance) of the number of O-2A progenitor cells and oligodendrocytes at different times after the start of experiment, but of the corresponding distributions as well. As our estimates show, there are scarcely any O-2A progenitor cells that divide in vitro more than twice before they acquire the competence for differentiation. Those O-2A cells that have undergone the critical divisions differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability. We give estimates of this probability for O-2A cells under different growth conditions. Our analysis suggests that the effect of thyroid hormone is twofold: it reduces the mean duration of the mitotic cycle for progenitor cells, and it increases the probability of their transformation into oligodendrocytes.

The shape of the hazard function in breast carcinoma: curability of the disease revisited.

BACKGROUND: The question of curability of breast carcinoma remains controversial. Because the probability of cure essentially is an asymptotic notion, the corresponding estimation problems call for special statistical methods. Such methods should account for an intimate connection between the probability of cure and the shape of the hazard function. METHODS: The study was performed on survival data for 13,166 women with breast carcinoma identified through the Utah Cancer Registry and stratified by clinical stage and age at diagnosis. For these patients, the follow-up period was 30 years. Three estimation procedures were used for estimating the hazard function from the data: the life table estimator, a kernel counterpart of the Nelson-Aalen estimator, and a parametric estimator specifically designed for two-component hazards. The parametric estimate of the hazard function was used to provide estimates of cure rates for each category of patients. RESULTS: For all categories of patients under study, the estimated hazard functions passed through a clear-cut maximum, showing a tendency to decrease as time approached the end of a follow-up period. The hazards appeared to be nonproportional across the strata. The estimated values of the cure rate and the corresponding confidence intervals were determined for each stratum of patients with breast carcinoma. CONCLUSIONS: The results of the current study strongly suggest that cure is a possible outcome of breast carcinoma treatment. The condition of proportionality of risks is not met in breast carcinoma survival data.

Modeling insight into spontaneous regression of tumors.

The phenomenon of spontaneous regression of benign and malignant tumors is well documented in the literature and is commonly attributed to the induction of apoptosis or activation of the immune system. We attempt at evaluating the role of random effects in this phenomenon. To this end, we consider a stochastic model of tumor growth which is descriptive of the fact that tumors are inherently prone to spontaneous regression due to the random nature of their development. The model describes a population of actively proliferating cells which may give rise to differentiated cells. The process of cell differentiation is irreversible and terminates in cell death. We formulate the model in terms of temporally inhomogeneous Markov branching processes with two types of cells so that the expected total number of neoplastic cells is consistent with the observed mean growth kinetics. Within the framework of this model, the extinction probability for proliferating cells tends to one as time tends to infinity. Given the event of nonextinction, the distribution of tumor size is asymptotically exponential. The limiting conditional distribution of tumor size is in good agreement with epidemiologic data on advanced lung cancer.

Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro.

As part of our attempts at understanding fundamental principles that underlie the generation of nondividing terminally differentiated progeny from dividing precursor cells, we have developed approaches to a quantitative analysis of proliferation and differentiation of oligodendrocyte type 2 astrocyte (O-2A) progenitor cells at the clonal level. Owing to extensive previous studies of clonal differentiation in this lineage, O-2A progenitor cells represent an excellent system for such an analysis. Previous studies have resulted in two competing hypotheses; one of them suggests that progenitor cell differentiation is symmetric, the other hypothesis introduces an asymmetric process of differentiation. We propose a general model that incorporates both such extreme hypotheses as special cases. Our analysis of experimental data has shown, however, that neither of these extreme cases completely explains the observed kinetics of O-2A progenitor cell proliferation and oligodendrocyte generation in vitro. Instead, our results indicate that O-2A progenitor cells become competent for differentiation after they complete a certain number of critical mitotic cycles that represent a period of symmetric development. This number varies from clone to clone and may be thought of as a random variable; its probability distribution was estimated from experimental data. Those O-2A cells that have undergone the critical divisions then may differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability, thereby exhibiting the asymmetric type of differentiation.

Eating patterns and risk of colon cancer.

Colon cancer has been associated with several nutrients and foods. The authors used data from a population-based study conducted in Northern California, Utah, and Minnesota to examine associations between dietary eating patterns and risk of developing colon cancer. Through factor analysis, detailed dietary intake data obtained from 1,993 cases (diagnosed in 1991-1994) and 2,410 controls were grouped into factors that were evaluated for relations with lifestyle characteristics and colon cancer risk. Several dietary patterns emerged. The dietary patterns with the most variation were labeled "Western," "prudent," "high fat/sugar dairy," "substituters," and "drinkers." The "Western" dietary pattern was associated with a higher body mass index and a greater intake of total energy and dietary cholesterol. The "prudent" pattern was associated with higher levels of vigorous leisure time physical activity, smaller body size, and higher intakes of dietary fiber and folate. Persons who had high scores on the "drinker" pattern were also more likely to smoke cigarettes. The "Western" dietary pattern was associated with an increased risk of colon cancer in both men and women. The association was strongest among people diagnosed prior to age 67 years (for men, odds ratio (OR)=1.96, 95% confidence interval (CI) 1.22-3.15; for women, OR=2.02, 95% CI 1.21-3.36) and among men with distal tumors (OR=2.25, 95% CI 1.47-3.46). The "prudent" diet was protective, with the strongest associations being observed among people diagnosed prior to age 67 years (men: OR=0.63, 95% CI 0.43-0.92; women: OR=0.58, 95% CI 0.38-0.87); associations with this dietary pattern were also strong among persons with proximal tumors (men: OR=0.55, 95% CI 0.38-0.80; women: OR=0.64, 95% CI 0.45-0.92). Although "substituters" (people who substituted low fat dairy products for high fat dairy products, margarine for butter, poultry for red meat, and whole grains for refined grains) were at reduced risk of colon cancer, the reduction in risk was not statistically significant. These data support the hypothesis that overall dietary intake pattern is associated with colon cancer, and that the dietary pattern associated with the greatest increase in risk is the one which typifies a Western-style diet.