The CRCgene database, which gathers all genetic association studies on colorectal cancer, allows for researchers to accurately interpret the risk factors of the disease and provides insight into the direction of further colorectal cancer research, according to a study published September 27 in the Journal of the National Cancer Institute.
Approximately 950,000 new cases of colorectal cancer are diagnosed each year. The risk of developing the disease also increases with age, and as life expectancy rises, the incidence continues to grow. These factors paired with rising health care costs have made both diagnosis and treatments for the disease costly. While diet and lifestyle may affect colorectal cancer incidence, so may genetic factors, and it is important to determine which genetic factors are most heavily associated with colorectal cancer incidence.
In order to determine the genetic factors associated with colorectal cancer, Julian Little, Ph.D., of the Department of Epidemiology and Community Medicine at the University of Ottawa and colleagues, gathered data from previously published guidelines for assessing cumulative evidence on genetic association studies, and performed meta-analyses on all the data, compiling all genetic association studies published in the field. The credibility of the studies was determined by the Venice criteria and the Bayesian False Discovery Probability (BFDP) test.
The researchers found 16 independent gene variants had the most highly credible links to colorectal cancer, with 23 variants. “The number of common, low-penetrance variants that appear to be associated with colorectal cancer is very much less than anticipated, therefore decreasing the feasibility of combining variants as a profile in a prediction tool for stratifying screening modalities on primary prevention approaches,” the authors write. Still, they feel that, “the analysis here provides a resource for mining available data and puts into context the sample sizes required for the identification of true associations.”
Background Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.
Methods We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan–Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period–specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
Results Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
Conclusion Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
Cumulative risks (percent) and corresponding 95% confidence intervals (CIs) of primary extracolonic cancers during the 10 and 20 years following diagnosis of colorectal cancer for carriers of mismatch repair gene mutations
|Cancer site||10 years||20 years|
|Risk, %||(95% CI)||Risk,%||(95% CI)|
|(0.87 to 3.17)||5.15||(2.86 to 7.68)|
|Urinary bladder||1.61||(0.65 to 2.75)||3.15||(1.37 to 5.20)|
|Small intestine||0.92||(0.28 to 1.73)||4.00||(1.92 to 6.41)|
|Stomach||0.66||(0.13 to 1.40)||1.15||(0.19 to 2.48)|
|Hepatobiliary tract†||0.83||(0.16 to 1.69)||1.42||(0.42 to 2.73)|
|Prostate||2.74||(0.86 to 4.77)||5.90||(2.69 to 9.76)|
|Endometrium||12.12||(7.66 to 17.11)||23.99||(16.79 to 32.84)|
|Breast||1.94||(0.58 to 3.83)||11.38||(0.63 to 16.69)|
|Ovary||0.94||(0.00 to 2.11)||2.08||(0.50 to 4.14)|
* Kidney etc. included kidney, renal pelvis, ureter and other and unspecified urinary organs.
† Hepatobiliary tract included liver and intrahepatic bile duct, gall bladder, and other and unspecified parts of biliary tract.
Patients who have had colorectal cancer and who are carriers of the DNA mismatch repair gene mutations that cause Lynch syndrome “have an increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers,” according to a study in the Journal of the National Cancer Institute.
Previous studies had shown that mutation carriers “are at a substantially increased risk of cancers of the colon, rectum, endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel, hepatobiliary tract, and pancreas,” the authors noted. A major inherited cancer syndrome, Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC).
The study was based on data for 764 patients from the Colon Cancer Family Registry, evenly divided between men and women, who were carriers of the mismatch repair gene mutation and previously diagnosed with colorectal cancer. Most of the carriers (52%) were recruited in Australia and New Zealand, with 33% from the United States and 15% from Canada. The average age at diagnosis of colorectal cancer was 44 years.
Compared with the general population, following colorectal cancer, carriers of mismatch repair gene mutations had a 70-fold increased risk for cancer of the small intestine, a 13-fold increased risk for cancer of the kidney, renal pelvis, and ureter or urethra, a 7-fold increased risk for cancer of the bladder, a 6-fold increased risk for hepatobiliary tract cancer, and a nearly 6-fold increased risk for gastric cancer. Men had a 2-fold increased risk of prostate cancer. The most common primary cancer following colorectal cancer for women with Lynch syndrome was endometrial cancer, with a 40-fold increased risk compared to the general population. There were 20 breast cancers and 6 ovarian cancers in the study population.
“These new data provide further determination of cancer risks, potentially informing and justifying ongoing studies to create the evidence for effective screening methodologies and intervals in [mismatch repair] gene mutation carriers,” the researchers concluded. “Larger studies are needed to refine risk estimates separately for specific [mismatch repair] gene mutations to best inform policies on clinical risk management.” ■
September 5, 2012 — People with a relatively low socioeconomic status account for a disproportionate number of colorectal cancers in the United States. Now, for the first time, a large prospective, observational study has shed light on the degree to which behavior and body mass contribute to this disparity.
Over one third of the excess risk…could be explained by differences in…behavioral risk factors.
“This study showed that over one third of the excess risk of invasive adenocarcinoma of the colon and rectum resulting from low [socioeconomic status] could be explained by differences in…behavioral risk factors, particularly in an unhealthy diet,” conclude the authors, led by Chyke A. Doubeni, MD, MPH, from the Department of Family Medicine and Community Health at the University of Pennsylvania Perelman School of Medicine in Philadelphia.
In addition to diet, Dr. Doubeni and colleagues found that physical inactivity, smoking, and being overweight are likely contributors to this risk.
In their study, published online September 5 in the Journal of the National Cancer Institute, the authors looked at health behaviors, obesity, and colorectal cancer risk among Americans of all socioeconomic statuses.
They used the National Institutes of Health-AARP Diet and Health Study as their data source. Specifically, they looked at middle-aged and elderly people from 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, Georgia and Detroit, Michigan). All of the participants enrolled in the study in 1995/96 and were followed through 2006. Health behaviors of the participants were determined using questionnaires.
Of the 506,488 study participants, 7676 developed colorectal cancer during the 10-year follow-up period.
How Class and Behavior/Body Mass Are Related
The authors evaluated the socioeconomic status of the participants in 2 ways: by census-tract data, which revealed “neighborhood socioeconomic status,” and by self-reported educational level (less than high school vs high school and more than high school).
On the basis of data from other studies on colorectal cancer and behavior, Dr. Doubeni and his team used statistical modeling to estimate the likely percentage of colorectal cancers mediated by behavioral risk factors.
They found that differences in socioeconomic status in the reported levels of physical inactivity, unhealthy diet, smoking, and unhealthy weight each explained between 11.3% and 21.6% of the association between education and risk for colorectal cancer, and between 8.6% and 15.3% of the association between neighborhood status and risk for colorectal cancer. Diet was found to have the biggest impact of all the health behaviors.
Overall, the combination of health behaviors and body mass index (BMI) explained approximately 43.9% (95% confidence interval [CI], 35.1% to 57.9%) of the association between risk for colorectal cancer and education and 36.2% (95% CI, 28.0% to 51.2%) of the association between the risk and neighborhood socioeconomic status.
In short, somewhere between one third and nearly one half of colorectal cancers among either low-income or less-than-high-school-educated Americans might be attributable to obesity and unhealthy behaviors.
However, a pair of experts not involved with the study do not find these results to be a cause for despair.
Instead, the study “demonstrates the intricate interplay” of socioeconomic and behavioral factors affecting colorectal cancer risk, write John Z. Ayanian, MD, and John M. Carethers, MD, in an accompanying editorial. Dr. Ayanian is from the Department of Health Care Policy at Harvard Medical School in Boston, Massachusetts, and Dr. Carethers is from the Department of Internal Medicine at the University of Michigan in Ann Arbor.
Public health practitioners can learn from these results, they believe. The study “underscores the need for more effective public health strategies to improve nutrition and physical activity in the United States and thereby curb the rising tide of obesity, particularly for those with less education and in disadvantaged communities,” the editorialists write.
Colon Cancer by Location
The study accounted for the anatomic location of the participants’ cancers (proximal colon, distal colon, or rectum), which resulted in one of the study’s “key findings,” according to the editorialists.
The health behaviors and BMI explained 95% of the association between education and the incidence of proximal colon cancer, but only 38% of the association between education and distal cancer and 24% of that between education and rectal cancer, Dr. Ayanian and Dr. Carethers point out.
That is a dramatic difference, they note. However, the editorialists think that these contrasting results for proximal and more distal cancers might “reflect the impact of an important omitted variable — colorectal cancer screening by socioeconomic status.”
Colorectal cancer screening has been shown to be more effective in reducing cancer incidence and mortality in the distal colon and rectum than in the proximal colon, the editorialists explain. Thus, this finding might have an easy explanation, they note.
“Because adults who are less educated and from less affluent communities are less likely to be screened, the greater effectiveness of screening for distal colorectal cancer may explain why socioeconomic gradients were much steeper for these anatomic sites than for proximal cancer,” they write.
The study was funded in part by the National Cancer Institute. The study authors and editorialists have disclosed no relevant financial relationships.
The association between breast and colorectal cancer in not clear. There is an increased incidence of breast cancer and colorectal hamartomas which may lead to colorectal cancer in PTEN-mutation spectrum disorders such as Cowden’s Syndrome, and in Peutz-Jeghers Syndrome. Data from genome-wide association studies demonstrates association of a common but low penetrance (weak) risk locus at chromosome 8q24.
The link between Lynch Syndrome has been controversial, but two recent studies have added weight to Lynch Syndrome as a risk factor for breast cancer. A recent study in JNCI (Win et al 2012) suggests that amongst Lynch Syndrome patients the risk of breast cancer as a second cancer after a diagnosis of colorectal cancer may be increased by about 76%. An earlier study this year suggests that their is molecular evidence for this association (Buerki et al Genes Chromosomes Cancer 2012).
Some studies in Li-Fraumeni Syndrome families identified mutations in CHEK2 as possible cause for this condition (Bell et al Science 1999). This link has not been reproducible but the variant 1100 may be a population variant which increases risk in Ashkenazi Jewish populations.
Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene. Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.
Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.