Health beliefs and endoscopic screening for colorectal cancer: potential for cancer prevention.

BACKGROUND: Colorectal cancer can be prevented through endoscopic removal of adenomatous polyps. Because screening endoscopy rates are low, it is critical to identify correlates of screening behavior that are amenable to interventions to improve screening rates. Our purpose was to identify the correlates of endoscopic screening among persons at risk for colorectal cancer. METHODS: We surveyed 1,160 healthy, adult, first-degree relatives of colorectal cancer patients in 583 kindreds, for a 43% response rate. Using multiple logistic regression analysis, we tested the association between screening behavior and perceived risk for colorectal cancer, the belief that colorectal cancer can be prevented, demographic factors, strength of family history, and practical barriers to screening. RESULTS: Persons screened at least once were older, were male, had stronger family histories, had a regular doctor, and had health insurance. After these fixed factors were accounted for, the belief that colorectal cancer can be prevented and higher perceived risk were associated with significantly greater odds of screening. CONCLUSIONS: This study establishes the need for trials evaluating the cancer prevention potential of the link between screening behavior and health beliefs. Physicians must be aware of their patients' family colorectal cancer history and recommend appropriate endoscopic screening for those at increased risk, particularly women. Patients should be educated about their cancer risk and about preventing colorectal cancer.

Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease.

Previous research by our group demonstrated a longitudinal change in caudate volume for symptomatic subjects with Huntington's disease (HD), and suggested that volume of the caudate may be a useful outcome measure for therapeutic studies in symptomatic patients. The current study was designed to determine whether longitudinal change in caudate atrophy could be documented in presymptomatic carriers of the HD gene mutation, and to compare rate of change in these subjects with rate of change in mildly and moderately affected symptomatic patients. We measured caudate volumes on serial magnetic resonance image scans from 30 patients at three stages of HD: 10 presymptomatic; 10 with mild symptoms, as indicated by scores on the Quantified Neurological Exam (QNE) < or =35; and 10 with moderate symptoms (QNE >45). The mean interscan interval was 36 months. When analyzed separately, both symptomatic groups and the presymptomatic group demonstrated a significant change in caudate volume over time. Amount of change over time did not differ significantly among the three groups. We conclude that change in caudate volume may be a useful outcome measure for assessing treatment effectiveness in both presymptomatic and symptomatic subjects.

Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington's disease.

The aim of this study was to examine basal ganglia volumes and regional cerebral blood flow in asymptomatic subjects at-risk for Huntington's disease who had undergone genetic testing. We determined which measures were the best 'markers' for the presence of the mutation and for the onset of symptoms. Twenty subjects who were Huntington's disease gene mutation-positive and 24 Huntington's disease gene mutation-negative participants, all of whom had a parent with genetically confirmed Huntington's disease, and were therefore 50% at-risk for inheriting the Huntington's disease gene mutation, were included in the study. To evaluate basal ganglia structure and function, MRI and single photon emission computed tomography (SPECT) were used. Quantitative measures of regional volumes and relative measures of regional perfusion were calculated. SPECT and MRI scans were co-registered so that MRI anatomy could be used accurately to place SPECT regions. Estimated years-to-onset in the mutation-positive subjects was calculated based on a regression formula that included gene (CAG)(n) repeat length and parental age of onset. Changes in imaging measures in relation to estimated years-to-onset were assessed. The imaging measure that was most affected in mutation-positive subjects was putamen volume. This was also the measure that correlated most strongly with approaching onset. In subjects >/=7 years from estimated onset age, the putamen volume measures were similar to those of the mutation-negative subjects. However, in subjects 90% discrimination from both the far-from-onset and the mutation-negative subjects. Caudate volume and bicaudate ratio also showed a significant decline in the close-to-onset subjects, although to a lesser degree than putamen volume reductions. Furthermore, SPECT basal ganglia perfusion deficits were observed in mutation-positive subjects. Imaging markers of neuropathological decline preceding clinical onset are important for assessing the effects of treatments aimed at slowing the course of Huntington's disease. The current study suggests that quantitative assessment of basal ganglia may provide a means to track early signs of decline in individuals with the Huntington's disease gene mutation prior to clinical onset.

Attitudes toward colon cancer gene testing: survey of relatives of colon cancer patients.

OBJECTIVES: Various studies have identified psychosocial factors that may influence attitudes toward colon cancer gene testing. Whereas family history of colon cancer has been associated with interest in gene testing, this has not been examined extensively. We hypothesized that the strength of family history of colon cancer is associated with risk perception and willingness to undergo gene testing. MATERIALS AND METHODS: We evaluated attitudes toward colon cancer gene testing among persons who had at least one first-degree relative with colon cancer. A total of 2680 at-risk relatives in 863 kindreds were identified and mailed an extensive survey regarding sociodemographic variables, family history, health behaviors and knowledge, and willingness to take a colon cancer gene test. A total of 56.6% of persons completed and returned surveys. We conducted a brief telephone survey of a random sample of 200 persons who did not respond to the mail survey. RESULTS: The combined study sample of 1373 people was 42% male, had a mean age of 55 +/- 15 years, was 96% white, and had moderate-to-high SES. A total of 77.4% were very likely to take the gene test, and 92.4% were somewhat or very likely to take the gene test. A total of 78% of the sample perceived a higher colon cancer risk, although patterns of risk perception and worry differed significantly between mail survey and telephone survey respondents. More of the telephone survey respondents were also somewhat unlikely or very unlikely to take the gene test compared to the mail survey respondents (13.7% versus 6.9%). In the combined sample, concern about developing colon cancer and risk perception increased with number of relatives with colon cancer (P < 0.0001). Eight percent expressed no concern about developing colon cancer; 4.8% felt their chance of developing colon cancer was lower than others of the same age, sex, and race; and 3.3% felt that they were very unlikely to develop colon cancer in their lifetime. However, there was strong interest in gene testing regardless of the number of affected relatives, and persons with more affected relatives were generally willing to pay more for the gene test (up to $1000). CONCLUSIONS: The strength of family history of colon cancer is associated with risk perception but not with willingness to undergo gene testing.

Attitudes toward colon cancer gene testing: factors predicting test uptake.

OBJECTIVES: Genetic discoveries in hereditary nonpolyposis colorectal cancer (HNPCC) have made possible genetic testing to determine susceptibility to this form of colorectal cancer (CRC). This study measured the uptake of genetic testing for HNPCC among first-degree relatives of CRC patients and conducted a preliminary analysis of the predictors of test uptake. MATERIALS AND METHODS: We compared 77 test acceptors and 181 decliners on demographic, medical history, and psychological characteristics, controlling for distance from the testing center. The psychological factors studied were risk perception for CRC, frequency of cancer thoughts, and perceived ability to cope with unfavorable genetic information. RESULTS: In the final regression model, after accounting for all variables, the significant predictors of test uptake were increased risk perception, greater perceived confidence in ability to cope with unfavorable genetic information, more frequent cancer thoughts, and having had at least one colonoscopy. The association between risk perception and uptake was dependent on frequency of cancer thoughts. Among those who thought about getting CRC more often, the probability of testing increased as perceived risk increased to approximately 50% likelihood of getting CRC and then leveled off. In contrast, among those who never or rarely thought about getting CRC, risk perception was unrelated to testing decision. CONCLUSIONS: Our findings are consistent with the associations reported between psychological factors and other cancer screening behaviors.

When does Huntington's disease begin?

Recent studies have detected basal ganglia atrophy in clinically asymptomatic persons with the genetic mutation that causes Huntington's disease (HD). Whether reductions in caudate and putamen volume on MRI scans are associated with changes in cognitive and neurologic functioning was examined in 13 healthy adults with the IT-15 mutation. Reduced striatal volume was found to correlate with greater neurologic (largely motor) impairment, slower mental processing speed, and poorer verbal learning, although none of the participants met even liberal criteria for clinical diagnosis of HD. These correlations are strikingly similar to those observed in symptomatic HD patients, possibly reflecting the earliest manifestations of disease.

Psychological opportunities and hazards in predictive genetic testing for cancer risk.

Although the availability of genetic tests seems like an unequivocally favorable turn of events, they are, in fact, not without controversy. At the center of the controversy is a question regarding the risks and benefits of genetic testing. Many geneticists, ethicists, psychologists, and persons at risk for cancer are concerned about the potentially adverse psychological effects of genetic testing on tested persons and their families. In addition, the screening and interventions that are useful in the general population remain to be shown effective in those with high genetic cancer risk. Consequently, there have been calls for caution in moving genetic testing out of research laboratories and into commercial laboratories until their impact and the effectiveness of cancer prevention strategies can be studied. This article examines the arguments and data for and against this caution, citing examples related to hereditary nonpolyposis colon cancer and drawing upon literature on testing for other genetic diseases.

Predictors of psychological adjustment to genetic testing for Huntington's disease.

In the present study the authors assessed predictors of adjustment to genetic testing for Huntington's disease. Fifty-two genetically positive and 108 genetically negative persons were studied for 1 year following testing. Adjustment, defined by hopelessness and depressive symptoms, was measured at 3, 6, 9, and 12 months after disclosure and was within normal limits for both groups. Those less well adjusted had tested positive, were married, had no children, or were closer to their estimated ages of onset. The study delineated risk factors for psychological distress that should be considered by people contemplating testing for Huntington's disease.

Neuropsychological stability over two years in asymptomatic carriers of the Huntington's disease mutation.

This study examined whether neuropsychological changes emerge over time in asymptomatic adults who have the Huntington's disease mutation. We also evaluated whether scores on cognitive tests or psychological symptom scales varied as a function of CAG repeat length or proximity to disease onset. Twenty two healthy "mutation positive" and 37 "mutation negative" adults completed cognitive tests and psychological rating scales before disclosure of their genetic test results and on an annual basis thereafter. Repeated measures ANOVAs analysed differences between the two groups over three assessments. Correlations of cognitive and psychological symptom test scores with estimated number of years to disease onset and CAG repeat length were computed. The two groups did not differ at study entry; nor did they differ in the rate of change over time. Tests of sustained attention and mental speed correlated with estimated years to disease onset, but not with repeat length. As a group, clinically asymptomatic adults with the Huntington's disease mutation do not display neuropsychological deficits when studied over a two year interval. However, persons who are likely nearing clinical onset of Huntington's disease may develop minor deficits in selected cognitive domains before they reach threshold for diagnosis.

Basal ganglia volume and proximity to onset in presymptomatic Huntington disease.

OBJECTIVE: To determine in presymptomatic individuals who carry the gene mutation for Huntington disease whether proximity to estimated age at onset is associated with volume of basal ganglia, as measured on magnetic resonance imaging scans. DESIGN: Survey study involving correlations between basal ganglia volume, measured blind to subject status, and estimation of subjects' age at onset. SETTING: Huntington's Disease Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 47 individuals at risk for Huntington disease (ie, off-spring of patients with Huntington disease). Twenty subjects tested positive for the gene mutation but were not symptomatic. Twenty-seven subjects tested negative. MAIN OUTCOME MEASURES: Estimated age at onset was calculated for each of 20 gene-positive individuals using an empirically derived formula based on the subject's trinucleotide repeat length and parental age at onset. Each subject's age at the time of the magnetic resonance imaging scan was subtracted from his or her estimated age at onset, yielding estimated years to onset. Volumes of caudate, putamen, and globus pallidus were measured on magnetic resonance imaging scans. RESULTS: After controlling for the subject's age at the time of the scan, significant correlations were found between volumes of all basal ganglia structures and years to onset. Gene-positive subjects who were far from onset had smaller basal ganglia volumes than gene-negative subjects for all structures except globus pallidus. Gene-positive subjects who were close to onset had smaller volumes than gene-negative subjects for all basal ganglia structures and had smaller volumes than subjects far from onset for all structures except caudate. CONCLUSIONS: The results suggest that atrophy of the basal ganglia occurs gradually, beginning years before symptom onset.

Genetic testing for cancer in children. Short-term psychological effect.

OBJECTIVE: To study the psychological effect of genetic testing in children. DESIGN: We evaluated the psychological effect of predictive genetic testing through surveys of children at risk for familial adenomatous polyposis. Their psychological state was assessed before testing and 3 months later. SETTING: A research clinic. PARTICIPANTS: A volunteer sample of 41 children, aged 6 to 16 years, and their parents. MAIN OUTCOME MEASURES: Self-report inventories of depression, anxiety, behavior problems, and competence. RESULTS: Nineteen children were found to have a gene mutation (mutation-positive) and 22 did not (mutation-negative). Their depression, anxiety, and behavior problem and competence scores remained in the normal range after testing. Also, parents' depression scores remained within normal limits at follow-up. There were subclinical changes, however. Mutation-positive children with affected mothers had significantly higher depression scores at follow-up. Also, regardless of test results, children with affected mothers had significantly increased anxiety scores after testing. In families with mutation-positive and mutation-negative children, familial adenomatous polyposis-unaffected parents experienced significantly increased depressive symptoms at follow-up. CONCLUSIONS: Predictive testing of children at risk for familial adenomatous polyposis did not lead to clinically significant psychological symptoms in tested children or their parents. However, it is premature to conclude that long-term follow-up will be equally favorable. Additional study will be needed to determine the families' understanding of the genetic information and the effect of the information on familial relationships.

Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease.

Huntington disease (HD) is an autosomal dominant degenerative disorder caused by an expanded and unstable trinucleotide repeat (CAG)n in a gene (IT-15) on chromosome 4. HD exhibits genetic anticipation--earlier onset in successive generations within a pedigree. From a population-based clinical sample, we ascertained parent-offspring pairs with expanded alleles, to examine the intergenerational behavior of the trinucleotide repeat and its relationship to anticipation. We find that the change in repeat length with paternal transmission is significantly correlated with the change in age at onset between the father and offspring. When expanded triplet repeats of affected parents are separated by median repeat length, we find that the longer paternal and maternal repeats are both more unstable on transmission. However, unlike in paternal transmission, in which longer expanded repeats display greater net expansion than do shorter expanded repeats, in maternal transmission there is no mean change in repeat length for either longer or shorter expanded repeats. We also confirmed the inverse relationship between repeat length and age at onset, the higher frequency of juvenile-onset cases arising from paternal transmission, anticipation as a phenomenon of paternal transmission, and greater expansion of the trinucleotide repeat with paternal transmission. Stepwise multiple regression indicates that, in addition to repeat length of offspring, age at onset of affected parent and sex of affected parent contribute significantly to the variance in age at onset of the offspring. Thus, in addition to triplet repeat length, other factors, which could act as environmental factors, genetic factors, or both, contribute to age at onset. Our data establish that further expansion of paternal repeats within the affected range provides a biological basis of anticipation in HD.

Psychological costs and benefits of predictive testing for Huntington's disease.

The impact of predictive genetic testing for Huntington's disease (HD) was assessed in 68 persons at high (n = 17) or low risk (n = 51) for the disease at one to six years following disclosure of test results. There was consensus in both groups that knowledge of HD genetic status was beneficial. A majority of persons felt relief from wondering and uncertainty. High-risk persons identified greater family closeness and financial security. For low-risk persons, the knowledge that their children were spared offered great consolation. Negative effects in high-risk persons were psychological burden (worry, guilt). Even for low-risk subjects, there was a period of adjustment and, in some, disappointment that low risk had not alleviated problems unrelated to HD. Although the majority of marriages were unaffected by testing, some persons in both groups reported that their marriages sustained positive or negative impact. Despite mixed consequences, most did not regret being tested. The benefits of testing appear to outweigh its drawbacks, at least among this self-selected group of research participants. We also must conclude, however, that predictive genetic testing will result in negative as well as positive consequences, regardless of test outcome.

Self-selection in predictive testing for Huntington's disease.

Several studies have reported favorable psychological reactions to predictive testing for Huntington's disease (HD). However, few at-risk persons have been tested, and there is evidence that some at-risk people avoid testing because they fear being unable to cope with the information. Favorable psychological reactions may result from self-selection of persons who believe they are better-equipped to handle "bad news." We surveyed 32 at-risk persons who had considered, but not chosen, testing and 66 persons who had been previously tested. Twelve persons decided not to be tested (No group); 20 persons postponed testing until some later date (Maybe group). Of the two untested groups, a significantly greater number of the No group had not been tested because they anticipated problems associated with their emotional reactions. The persons in the Tested group had less often anticipated problems with their emotional reactions; and among the minority who had anticipated some problems, most did not question their ability to cope. We conclude that the Tested persons are psychologically selected for favorable responses to genetic testing. Surveys of health professionals suggest that a sizable minority would disclose genetic disease risk whether or not people want it. Thus, people who would not choose to be tested might be persuaded to do so, or have results thrust upon them. We should be wary about assuming that the generally favorable reactions to HD testing will continue when testing becomes more widespread, as is likely to happen with simplification of the technology and acceptance of these tests by the medical community.

Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons.

Previous investigations using linear CT measures found no evidence of caudate atrophy in asymptomatic persons who have the DNA haplotype linked to the Huntington's disease (HD) gene. We measured volumes of the caudate, putamen, and globus pallidus on MRIs of 10 gene marker-positive and 18 gene marker-negative asymptomatic at-risk persons. The volumes of all basal ganglia structures were significantly reduced in the marker-positive group, even after controlling for age, total brain volume, and minor neurologic signs. Discriminant function analysis using basal ganglia volumes and age as predictor variables correctly identified genetic status in 86% of subjects. These results indicate that basal ganglia volume is reduced before individuals become symptomatic with HD.

Unimpaired verbal memory and oculomotor control in asymptomatic adults with the genetic marker for Huntington's disease.

OBJECTIVE: To determine whether asymptomatic individuals at very high genetic risk for Huntington's disease (HD) have demonstrable cognitive or oculomotor abnormalities. DESIGN: A case-control study was employed. Presence of the chromosome-4 DNA marker linked to the HD phenotype was the criterion for HD risk. SETTING: The Baltimore Huntington's Disease Project Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PARTICIPANTS: Seventy-six asymptomatic adults at risk for HD, voluntarily enrolled for genetic testing, and determined by clinical examination to be free of major psychiatric disorder or evidence of HD. Twenty were determined to be at greater than or equal to 95% risk for HD; 56 were at less than or equal to 5% risk [corrected]. MEASURES: The Hopkins Verbal Learning Test was used to assess verbal learning and memory. Oculomotor functioning was assessed using Novel-Stimulus, Mirror-Stimulus, and Predictive-Saccade paradigms. Outcome measures included number of correctly recalled words, recognition accuracy, and response bias, as well as saccade latency and number of errors on the Mirror-Stimulus Test. RESULTS: With one exception, all participants performed within the normal range on the Hopkins Verbal Learning Test. In a blind follow-up examination of the individual who performed aberrantly on the Hopkins Verbal Learning Test, she exhibited neurologic and psychiatric changes sufficient for a clinical diagnosis of HD. There were no group differences on the tests of oculomotor functioning. CONCLUSIONS: Young, asymptomatic adults at very high genetic risk for HD are unimpaired in tests of verbal learning and memory and oculomotor functioning.