Risk of developing colorectal cancer following a negative colonoscopy examination: evidence for a 10-year interval between colonoscopies

Context  Limited evidence exists to guide the optimal frequency of repeat endoscopic examination for colorectal cancer screening after a negative colonoscopy. Objective  To determine the duration and magnitude of the risk of developing colorectal cancer following performance of a negative colonoscopy. Design, Setting, and Patients  Population-based retrospective analysis of individuals whose colonoscopy evaluations did not result in a diagnosis of colorectal neoplasia. Patients who had been evaluated between April 1, 1989, and December 31, 2003, were identified using Manitoba Health's physician billing claims database (N = 35 975). Standardized incidence ratios (SIRs) were calculated to compare colorectal cancer incidence in our cohort with colorectal cancer incidence in the provincial population. Stratified analysis was performed to determine the duration of the reduced risk. Patients with a history of colorectal cancer prior to the index colonoscopy, inflammatory bowel disease, resective colorectal surgery, and lower gastrointestinal endoscopy within the 5 years before the index colonoscopy were excluded. Cohort members were followed up from the time of the index colonoscopy until diagnosis of colorectal cancer, death, out-migration from Manitoba, or end of the study period on December 31, 2003. Main Outcome Measure  Incidence of colorectal cancer. Results  A negative colonoscopy was associated with SIRs of 0.69 (95% confidence interval [CI], 0.59-0.81) at 6 months, 0.66 (95% CI, 0.56-0.78) at 1 year, 0.59 (95% CI, 0.48-0.72) at 2 years, 0.55 (95% CI, 0.41-0.73) at 5 years, and 0.28 (95% CI, 0.09-0.65) at 10 years. The proportion of colorectal cancer located in the right side of the colon was significantly higher in the colonoscopy cohort than the rate in the Manitoba population (47% vs 28%; P<.001). Conclusions  The risk of developing colorectal cancer remains decreased for more than 10 years following the performance of a negative colonoscopy. There is a need to improve the early detection rate of right-sided colorectal neoplasia in usual clinical practice.      

Magnesium intake in relation to risk of colorectal cancer in women

Context  Animal studies have suggested that dietary magnesium may play a role in the prevention of colorectal cancer, but data in humans are lacking. Objective  To evaluate the hypothesis that a high magnesium intake reduces the risk of colorectal cancer in women. Design, Setting, and Participants  The Swedish Mammography Cohort, a population-based prospective cohort of 61 433 women aged 40 to 75 years without previous diagnosis of cancer at baseline from 1987 to 1990. Main Outcome Measure  Incident invasive colorectal cancer. Results  During a mean of 14.8 years (911 042 person-years) of follow-up, 805 incident colorectal cancer cases were diagnosed. After adjustment for potential confounders, we observed an inverse association of magnesium intake with the risk of colorectal cancer (P for trend = .006). Compared with women in the lowest quintile of magnesium intake, the multivariate rate ratio (RR) was 0.59 (95% confidence interval [CI], 0.40-0.87) for those in the highest quintile. The inverse association was observed for both colon (RR, 0.66; 95% CI, 0.41-1.07) and rectal cancer (RR, 0.45; 95% CI, 0.22-0.89). Conclusion  This population-based prospective study suggests that a high magnesium intake may reduce the occurrence of colorectal cancer in women.      

Increasing incidence of thyroid cancer in the United States, 1973-2002

Context  Increasing cancer incidence is typically interpreted as an increase in the true occurrence of disease but may also reflect changing pathological criteria or increased diagnostic scrutiny. Changes in the diagnostic approach to thyroid nodules may have resulted in an increase in the apparent incidence of thyroid cancer. Objective  To examine trends in thyroid cancer incidence, histology, size distribution, and mortality in the United States. Methods  Retrospective cohort evaluation of patients with thyroid cancer, 1973-2002, using the Surveillance, Epidemiology, and End Results (SEER) program and data on thyroid cancer mortality from the National Vital Statistics System. Main Outcome Measures  Thyroid cancer incidence, histology, size distribution, and mortality. Results  The incidence of thyroid cancer increased from 3.6 per 100 000 in 1973 to 8.7 per 100 000 in 2002—a 2.4-fold increase (95% confidence interval [CI], 2.2-2.6; P<.001 for trend). There was no significant change in the incidence of the less common histological types: follicular, medullary, and anaplastic (P>.20 for trend). Virtually the entire increase is attributable to an increase in incidence of papillary thyroid cancer, which increased from 2.7 to 7.7 per 100 000—a 2.9-fold increase (95% CI, 2.6-3.2; P<.001 for trend). Between 1988 (the first year SEER collected data on tumor size) and 2002, 49% (95% CI, 47%-51%) of the increase consisted of cancers measuring 1 cm or smaller; 87% (95% CI, 85%-89%) consisted of cancers measuring 2 cm or smaller. Mortality from thyroid cancer was stable between 1973 and 2002 (approximately 0.5 deaths per 100 000). Conclusions  The increasing incidence of thyroid cancer in the United States is predominantly due to the increased detection of small papillary cancers. These trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable overall mortality, suggest that increasing incidence reflects increased detection of subclinical disease, not an increase in the true occurrence of thyroid cancer.      

Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence?

Context  The debate about the efficacy of prostate-specific antigen (PSA) screening for prostate cancer has received substantial attention in the medical literature and the media, but the extent to which men are actually screened is unknown. If practice were evidence-based, PSA screening would be less common among men than colorectal cancer screening, a preventive service of broad acceptance and proven efficacy. Objective  To compare the prevalences of PSA and colorectal cancer screening among US men. Design, Setting, and Population  The 2001 Behavioral Risk Factor Surveillance System, an annual population-based telephone survey of US adults conducted by the Centers for Disease Control and Prevention, was used to gather data on a representative sample of men aged 40 years or older from all 50 states and the District of Columbia (n = 49 315). Main Outcome Measures  Proportions of men ever screened and up to date on screening for prostate cancer (with PSA testing) and colorectal cancer (with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy). Results  Overall, men are more likely to report having ever been screened for prostate cancer than for colorectal cancer; 75% of those aged 50 years or older have had a PSA test vs 63% for any colorectal cancer test (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.18-1.21). Up-to-date PSA screening is also more common than colorectal cancer screening for men of all ages. Among men aged 50 to 69 years (those for whom there is the greatest consensus in favor of screening), 54% reported an up-to-date PSA screen, while 45% reported up-to-date testing for colorectal cancer (RR, 1.19; 95% CI, 1.16-1.21). In state-level analyses of this age group, men were significantly more likely to be up to date on prostate cancer screening compared with colorectal cancer screening in 27 states, while up-to-date colorectal cancer screening was more common in only 1 state. Conclusion  Among men in the United States, prostate cancer screening is more common than colorectal cancer screening. Physicians should ensure that men who choose to be screened for cancer are aware of the known mortality benefit of colorectal cancer screening and the uncertain benefits of screening for prostate cancer.      

Association of family history with cancer recurrence and survival among patients with stage III colon cancer

Jennifer A. Chan, MD, MPH; Jeffrey A. Meyerhardt, MD, MPH; Donna Niedzwiecki, PhD; Donna Hollis, MS; Leonard B. Saltz, MD; Robert J. Mayer, MD; James Thomas, MD, PhD; Paul Schaefer, MD; Renaud Whittom, MD; Alexander Hantel, MD; Richard M. Goldberg, MD; Robert S. Warren, MD; Monica Bertagnolli, MD; Charles S. Fuchs, MD, MPH

JAMA. 2008;299(21):2515-2523.

Context  A family history of colorectal cancer in a first-degree relative increases the risk of developing colorectal cancer. However, the influence of family history on cancer recurrence and survival among patients with established disease remains uncertain.

Objective  To examine the association of family history of colorectal cancer with cancer recurrence and survival of patients with colon cancer.

Design, Setting, and Participants  Prospective observational study of 1087 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients provided data on family history at baseline and were followed up until March 2007 for disease recurrence and death (median follow-up, 5.6 years). In a subset of patients, we assessed microsatellite instability (MSI) and expression of the mismatch repair (MMR) proteins MLH1 and MSH2 in tumor specimens.

Main Outcome Measures  Disease-free survival, recurrence-free survival, and overall survival according to the presence or absence of a family history of colorectal cancer.

Results  Among 1087 eligible patients, 195 (17.9%) reported a family history of colorectal cancer in a first-degree relative. Cancer recurrence or death occurred in 57 of 195 patients (29%; 95% confidence interval [CI], 23%-36%) with a family history of colorectal cancer and 343 of 892 patients (38%; 95% CI, 35%-42%) without a family history. Compared with patients without a family history, the adjusted hazard ratios (HRs) among those with 1 or more affected first-degree relatives were 0.72 (95% CI, 0.54-0.96) for disease-free survival, 0.74 (95% CI, 0.55-0.99) for recurrence-free survival, and 0.75 (95% CI, 0.54-1.05) for overall survival. This reduction in risk of cancer recurrence or death associated with a family history became stronger with an increasing number of affected first-degree relatives. Compared with participants without a family history of colorectal cancer, those with 1 affected relative had a multivariate HR of 0.77 (95% CI, 0.57-1.04) for disease-free survival. For participants with 2 or more affected relatives, we observed a greater reduction in risk (multivariate HR for disease-free survival, 0.49; 95% CI, 0.23-1.04; P for trend with increasing number of affected relatives = .01). The improved disease-free survival associated with a family history was independent of tumoral MSI or MMR status.

Conclusion  Among patients with stage III colon cancer receiving adjuvant chemotherapy, a family history of colorectal cancer is associated with a significant reduction in cancer recurrence and death.

     

Prediction of germline mutations and cancer risk in the Lynch syndrome

Context  Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost. Objective  To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer. Design, Setting, and Patients  External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability. Main Outcome Measure  Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy. Results  In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines. Conclusions  MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.      

Colorectal cancer screening: scientific review

Context  Screening for colorectal cancer clearly reduces colorectal cancer mortality, yet many eligible adults remain unscreened. Several screening tests are available, and various professional organizations have differing recommendations on which screening test to use. Clinicians are challenged to ensure that eligible patients undergo colorectal cancer screening and to guide patients in choosing what tests to receive. Objective  To critically assess the evidence for use of the available colorectal cancer screening tests, including fecal occult blood tests, sigmoidoscopy, colonoscopy, double-contrast barium enema, and newer tests, such as virtual colonoscopy and stool-based molecular screening. Data Sources  All relevant English-language articles were identified using PubMed (January 1966-August 2002), published meta-analyses, reference lists of key articles, and expert consultation. Data Extraction  Studies that evaluated colorectal cancer screening in healthy individuals and assessed clinical outcomes were included. Evidence from randomized controlled trials was considered to be of highest quality, followed by observational evidence. Diagnostic accuracy studies were evaluated when randomized controlled trials and observational studies were not available or did not provide adequate evidence. Studies were excluded if they did not evaluate colorectal screening tests and if they did not evaluate average-risk individuals. Data Synthesis  Randomized controlled trials have shown that fecal occult blood testing can reduce colorectal cancer incidence and mortality. Case-control studies have shown that sigmoidoscopy is associated with a reduction in mortality, and observational studies suggest colonoscopy is effective as well. Combining fecal occult blood testing and sigmoidoscopy may decrease mortality and can increase diagnostic yield. Conclusion  The recommendation that all men and women aged 50 years or older undergo screening for colorectal cancer is supported by a large body of direct and indirect evidence. At present, the available evidence does not currently support choosing one test over another.      

Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial

Context  Observational studies and polyp recurrence trials are not conclusive regarding the effects of a low-fat dietary pattern on risk of colorectal cancer, necessitating a primary prevention trial. Objective  To evaluate the effects of a low-fat eating pattern on risk of colorectal cancer in postmenopausal women. Design, Setting, and Participants  The Women’s Health Initiative Dietary Modification Trial, a randomized controlled trial conducted in 48 835 postmenopausal women aged 50 to 79 years recruited between 1993 and 1998 from 40 clinical centers throughout the United States. Interventions  Participants were randomly assigned to the dietary modification intervention (n = 19 541; 40%) or the comparison group (n = 29 294; 60%).The intensive behavioral modification program aimed to motivate and support reductions in dietary fat, to increase consumption of vegetables and fruits, and to increase grain servings by using group sessions, self-monitoring techniques, and other tailored and targeted strategies. Women in the comparison group continued their usual eating pattern. Main Outcome Measure  Invasive colorectal cancer incidence. Results  A total of 480 incident cases of invasive colorectal cancer occurred during a mean follow-up of 8.1 (SD, 1.7) years. Intervention group participants significantly reduced their percentage of energy from fat by 10.7% more than did the comparison group at 1 year, and this difference between groups was mostly maintained (8.1% at year 6). Statistically significant increases in vegetable, fruit, and grain servings were also made. Despite these dietary changes, there was no evidence that the intervention reduced the risk of invasive colorectal cancer during the follow-up period. There were 201 women with invasive colorectal cancer (0.13% per year) in the intervention group and 279 (0.12% per year) in the comparison group (hazard ratio, 1.08; 95% confidence interval, 0.90-1.29). Secondary analyses suggested potential interactions with baseline aspirin use and combined estrogen-progestin use status (P = .01 for each). Colorectal examination rates, although not protocol defined, were comparable between the intervention and comparison groups. Similar results were seen in analyses adjusting for adherence to the intervention. Conclusion  In this study, a low-fat dietary pattern intervention did not reduce the risk of colorectal cancer in postmenopausal women during 8.1 years of follow-up. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00000611      

Cancer incidence before and after kidney transplantation

Context  Immune suppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer and a few virus-associated cancers. Although it is generally accepted that other cancers do not occur at increased rates, there have been few long-term population-based cohort studies performed. Objective  To compare the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression: during dialysis and during end-stage kidney disease before renal replacement therapy (RRT). Design, Setting, and Participants  A population-based cohort study of 28 855 patients with end-stage kidney disease who received RRT, with 273 407 person-years of follow-up. Incident cancers (1982-2003) were ascertained by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Main Outcome Measure  Standardized incidence ratios (SIRs) of cancer, using age-specific, sex-specific, calendar year–specific, and state/territory–specific population cancer incidence rates. Results  The overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1236; SIR, 3.27; 95% confidence interval [CI], 3.09-3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27-1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08-1.25). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology. Conclusions  Kidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites. Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.      

Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer

Context  Randomized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia. However, data on long-term risk of colorectal cancer according to dose, timing, or duration of therapy with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) remain limited. Objective  To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer. Design, Setting, and Participants  Prospective cohort study of 82 911 women enrolled in the Nurses’ Health Study providing data on medication use biennially since 1980 and followed up through June 1, 2000. Main Outcome Measure  Incident colorectal cancer. Results  Over a 20-year period, we documented 962 cases of colorectal cancer. Among women who regularly used aspirin (2 standard [325-mg] tablets per week), the multivariate relative risk (RR) for colorectal cancer was 0.77 (95% confidence interval [CI], 0.67-0.88) compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use (P.001 for trend). The benefit appeared related to dose: compared with women who reported no use, the multivariate RRs for cancer were 1.10 (95% CI, 0.92-1.31) for women who used 0.5 to 1.5 standard aspirin tablets per week, 0.89 (95% CI, 0.73-1.10) for 2 to 5 aspirin per week, 0.78 (95% CI, 0.62-0.97) for 6 to 14 aspirin per week, and 0.68 (95% CI, 0.49-0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 (95% CI, 0.31-0.71). A similar dose-response relationship was found for nonaspirin NSAIDs (P = .007 for trend). The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week. Conclusions  Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered.      

Statins and cancer risk: a meta-analysis

Context  Statins are cholesterol-lowering drugs that have been proven in randomized controlled trials to prevent cardiac events. Recent retrospective analyses have suggested that statins also prevent cancer. Objectives  To investigate the effect of statin therapy on cancer incidence and cancer death and to analyze the effect of statins on specific cancers and the effect of statin lipophilicity or derivation. Data Sources  A systematic literature search of MEDLINE, EMBASE, CINAHL, Web of Science, CANCERLIT, and the Cochrane Systematic Review Database through July 2005 was conducted using specific search terms. A review of cardiology and cancer abstracts and manual review of references was also performed. Study Selection  Twenty-seven of the 8943 articles (n = 86 936 participants) initially identified met the inclusion criteria, reporting 26 randomized controlled trials of statins, with a mean duration of follow-up of at least 1 year, enrolling a minimum of 100 patients, and reporting data on either cancer incidence (n = 20 studies) or cancer death (n = 22 studies). Data Extraction  All data were independently extracted by 3 investigators using a standardized data abstraction tool. Weighted averages were reported as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model (DerSimonian and Laird methods). Statistical heterogeneity scores were assessed with the Q statistic. Data Synthesis  In meta-analyses including 6662 incident cancers and 2407 cancer deaths, statins did not reduce the incidence of cancer (OR, 1.02; 95% CI, 0.97-1.07) or cancer deaths (OR, 1.01; 95% CI, 0.93-1.09). No reductions were noted for any individual cancer type. This null effect on cancer incidence persisted when only hydrophilic, lipophilic, naturally derived, or synthetically derived statins were evaluated. Conclusions  Statins have a neutral effect on cancer and cancer death risk in randomized controlled trials. We found that no type of cancer was affected by statin use and no subtype of statin affected the risk of cancer.      

Risk of lung cancer among white and black relatives of individuals with early-onset lung cancer

Context  Evidence exists that lung cancer aggregates in families and recent findings of a chromosomal region linked to lung cancer susceptibility support a genetic component to risk. Family studies of early-onset lung cancer patients offer a unique opportunity to evaluate lifetime risk of lung cancer in relatives. Objective  To measure lung cancer aggregation and estimate lifetime risk among relatives of early-onset cases and population-based controls. Design and Setting  Familial aggregation and cumulative risk estimates from interview data of incident cases and concurrently ascertained controls between 1990 and 2003 in metropolitan Detroit, Mich. Participants  The study included 7576 biological mothers, fathers, and siblings of 692 early-onset cases and 773 frequency-matched controls. One third of the population was black. Main Outcome Measures  Cumulative lifetime risk of lung cancer, stratified by race and smoking behavior in relatives of early-onset cases and controls. Results  Smokers with a family history of early-onset lung cancer in a first-degree relative had a higher risk of developing lung cancer with increasing age than smokers without a family history. An increase in risk occurs after age 60 years in these individuals, with 17.1% (SE 2.4%) of white case relatives and 25.1% (SE 5.8%) of black case relatives diagnosed with lung cancer by age 70 years. Relatives of black cases were at statistically significant increased risk of lung cancer compared with relatives of white cases (odds ratio, 2.07, 95% confidence interval, 1.29-3.32) after adjusting for age, sex, pack-years, pneumonia, and chronic obstructive lung disease. Conclusions  First-degree relatives of black individuals with early-onset lung cancer have greater risk of lung cancer than their white counterparts, and these risks are further amplified by cigarette smoking. These data provide estimates of lung cancer risk that can be used to offer counseling to family members of patients with early-onset lung cancer.      

Somatic acquisition and signaling of TGFBR1*6A in cancer

Context  TGFBR1*6A is a common polymorphism of the type I transforming growth factor receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. Objectives  To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3–amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients  Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures  TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-–dependent cell proliferation. Results  TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF- growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions  TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF- signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.      

Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies

Context  Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. Objective  To evaluate the association between dietary fiber intake and risk of colorectal cancer. Design, Setting, and Participants  From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725 628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. Main Outcome Measure  Incident colorectal cancer. Results  During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). Conclusions  In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.      

Estimating risk of cancer associated with radiation exposure from 64-slice computed tomography coronary angiography

Context  Computed tomography coronary angiography (CTCA) has become a common diagnostic test, yet there are little data on its associated cancer risk. The recent Biological Effects of Ionizing Radiation (BEIR) VII Phase 2 report provides a framework for estimating lifetime attributable risk (LAR) of cancer incidence associated with radiation exposure from a CTCA study, using the most current data available on health effects of radiation. Objectives  To determine the LAR of cancer incidence associated with radiation exposure from a 64-slice CTCA study and to evaluate the influence of age, sex, and scan protocol on cancer risk. Design, Setting, and Patients  Organ doses from 64-slice CTCA to standardized phantom (computational model) male and female patients were estimated using Monte Carlo simulation methods, using standard spiral CT protocols. Age- and sex-specific LARs of individual cancers were estimated using the approach of BEIR VII and summed to obtain whole-body LARs. Main Outcome Measures  Whole-body and organ LARs of cancer incidence. Results  Organ doses ranged from 42 to 91 mSv for the lungs and 50 to 80 mSv for the female breast. Lifetime cancer risk estimates for standard cardiac scans varied from 1 in 143 for a 20-year-old woman to 1 in 3261 for an 80-year-old man. Use of simulated electrocardiographically controlled tube current modulation (ECTCM) decreased these risk estimates to 1 in 219 and 1 in 5017, respectively. Estimated cancer risks using ECTCM for a 60-year-old woman and a 60-year-old man were 1 in 715 and 1 in 1911, respectively. A combined scan of the heart and aorta had higher LARs, up to 1 in 114 for a 20-year-old woman. The highest organ LARs were for lung cancer and, in younger women, breast cancer. Conclusions  These estimates derived from our simulation models suggest that use of 64-slice CTCA is associated with a nonnegligible LAR of cancer. This risk varies markedly and is considerably greater for women, younger patients, and for combined cardiac and aortic scans.      

Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. Objective  To examine the effect of aspirin on the risk of cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. Intervention  A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day. Main Outcome Measures  Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. Results  No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. Conclusions  Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.      

Association between BRCA1 mutations and ratio of female to male births in offspring of families with breast cancer,ovarian cancer,or both

Context  Defects in X-chromosome inactivation distort sex ratio in mice. The BRCA1 gene is also involved in X-chromosome inactivation, suggesting the possibility that some sex-ratio distortion may be associated with BRCA1-related human cancer syndromes. Objective  To determine whether BRCA1 mutations are associated with distortion of the sex ratio of births in families with breast cancer, ovarian cancer, or both. Design and Setting  Analysis of germline mutations in participants from Spain who had been screened for BRCA between 1998 and 2002. Participants  Sixty-eight families with at least 3 breast cancer cases or ovarian cancer cases, or both types of cancer in 2 generations (germline mutations: BRCA1, n = 17; BRCA2, n = 15; and BRCA unrelated, n = 36). An average of 4 relatives per family were tested for the corresponding BRCA mutation. Main Outcome Measure  Male and female births registered in breast and/or ovarian pedigrees tested for the presence of BRCA1 and BRCA2 germline mutations. Results  Of BRCA1-related breast and/or ovarian cancer pedigrees, there was a 2-fold excess of female births (218 female vs 109 male births). Of BRCA2-related or BRCA-unrelated breast and/or ovarian cancer pedigrees, there was not an excess of female births (175 female/150 male and 344 female/315 male, respectively). Of 327 BRCA1 births, 218 (67%) were female births compared with 54% among BRCA2 pedigrees (175/327; P<.001) and 52% among BRCA-unrelated pedigrees (344/659; P<.001). Female births increased in the offspring of BRCA1 carriers compared with BRCA2 carriers (67% vs 52%; P = .004). Conclusion  In these families with breast and/or ovarian cancer, mutations in BRCA1 but not BRCA2 were associated with a sex ratio skewed against male births.      

Caloric restriction and incidence of breast cancer

Context  Restricting caloric intake is one of the most effective ways to extend lifespan and to reduce spontaneous tumor occurrence in experimental animals, but whether similar associations hold in humans has not been appropriately studied. Objective  To determine whether caloric restriction in early life reduces the risk of invasive breast cancer. Design, Setting, and Participants  Retrospective cohort study using data from the Swedish Inpatient Registry, the Swedish Cancer Registry, the Swedish Death Registry, and the Swedish Fertility Registry. Participants were 7303 Swedish women hospitalized for anorexia nervosa prior to age 40 years between 1965 and 1998. Women were excluded (n = 31) if they were diagnosed with cancer prior to their first discharge from hospitalization for anorexia nervosa. Main Outcome Measure  Incidence of invasive breast cancer. Results  Compared with the Swedish general population, women hospitalized for anorexia nervosa prior to age 40 years had a 53% (95% confidence interval [CI], 3%-81%) lower incidence of breast cancer; nulliparous women with anorexia nervosa had a 23% (95% CI, 79% higher to 75% lower) lower incidence, and parous women with anorexia nervosa had a 76% (95% CI, 13%-97%) lower incidence. Conlusions  Severe caloric restriction in humans may confer protection from invasive breast cancer. Low caloric intake prior to first birth followed by a subsequent pregnancy appears to be associated with an even more pronounced reduction in risk.      

History and molecular genetics of Lynch syndrome in family G: a century later

Context  In 1895, Aldred Scott Warthin, MD, PhD, initiated one of the most thoroughly documented and longest cancer family histories ever recorded. The unusually high incidence and segregation of cancers of the colon, rectum, stomach, and endometrium in Dr Warthin’s family G was later followed up by his colleagues, most recently by Henry Lynch, MD. Described today as a Lynch syndrome family, family G was last documented in 1971, prior to the modern era of molecular diagnostics. Objective  To update family G. Design, Setting, and Participants  Historical prospective cohort study of family G members from 1895 to 2000. Main Outcome Measures  The primary outcomes were the frequencies and types of cancers, ages at diagnosis, and presence of the T to G transversion at the splice acceptor site of exon 4 of the mutS homolog 2, colon cancer, nonpolyposis type 1 (E coli) (MSH2) gene in family G members. A secondary analysis compared cancer-specific incidence rates in family G with published national and regional cancer incidence rates through the standardized incidence ratio (SIR). Results  Family G now has 929 known descendants of the original progenitor first reported in 1913. Cancers of the colon and rectum (SIR, 3.20; 95% confidence interval [CI], 2.39-4.19) and endometrium (SIR, 3.51; 95% CI, 1.92-5.89) continue to predominate in family G. Five of 40 tested members of family G carry the MSH2 T to G mutation; as a result, 15 of their living relatives are at increased risk of developing 1 or more colorectal or Lynch syndrome–associated cancers. In contrast, 97 living members of family G can now be excluded as mutation carriers. Conclusion  Within the last decade, molecular diagnostic testing has transformed the care of family G and other Lynch syndrome families in which a pathogenic mutation has been identified.