Katja Aktan-Collan

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

Ten Years After Mutation Testing for Lynch Syndrome: Cancer Incidence and Outcome in Mutation-Positive and Mutation-Negative Family Members

PURPOSE Colonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago. MATERIALS AND METHODS Cancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type. RESULTS Compliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased. CONCLUSION Long-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.

Psychological consequences of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC): A prospective follow-up study

Predictive genetic testing for cancer allows identification of those with the mutation (mutation positive) who should undergo cancer surveillance aiming at early detection of cancer and those without the mutation (mutation negative), whose unnecessary worry can be alleviated and who need not undergo frequent surveillance. However, there is a risk that predictive testing might have a harmful emotional impact on an individual. In the course of a predictive genetic testing protocol, we assessed general anxiety (by the State‐Trait Anxiety Inventory [STAI]), fear of cancer and death, satisfaction with life and attitude to the future using a questionnaire survey in 271 individuals tested for hereditary non‐polyposis colorectal cancer (HNPCC). Measurements were made before the first counseling (baseline), at the test disclosure session (STAI only) and 1 and 12 months after disclosure. Although at every measurement, the mutation‐positive individuals were more afraid of cancer than those who were mutation negative, in both groups fear of cancer decreased significantly from baseline after disclosure. The mutation‐positive subjects were more anxious than their counterparts immediately after the test disclosure, but the differences had disappeared at the follow‐ups. In other variables, neither differences between the groups defined by mutation status nor changes with time were detected. Our findings suggest that counseling and testing relieve fear of cancer; no harmful emotional impact was detectable at the 1‐year follow‐up. To confirm these findings, however, the impact of testing should be studied after a longer interval. Furthermore, to evaluate the ultimate interpretation of these results, studies are needed to investigate the impact of fear of cancer on surveillance behavior among the mutation‐positive subjects.

Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction.

The aim of this prospective study was to assess the uptake of predictive genetic testing for hereditary non‐polyposis colorectal cancer (HNPCC) and its associations with sociodemographic and other factors, and long‐term satisfaction with taking the test. The test was offered to all high‐risk members (n = 446) of 36 Finnish HNPCC families in which the mutation was known. The procedure comprised an educational counselling session, a period for reflection, and a test disclosure session. Data were collected by questionnaires sent before the educational counselling and 1 month and 1 year after the test disclosure. Of those eligible, 85% (n = 381) completed the first questionnaire study. Non‐participation was more common among men living alone who had not participated in the clinical cancer surveillance programme. Of the 347 subjects who attended counselling, 334 (75% of all subjects) were actually tested. After logistic‐regression analysis, the only significant factor predicting test acceptance proved to be employment status: those employed were more likely than others to accept the test (odds ratio = 2.25; 95% confidence intervals, 1.09 to 4.61). At follow‐up, over 90% of the subjects were fully satisfied with the decision to take the test. In conclusion, acceptance of the test was considerably higher than in previously reported studies. We attribute this to our careful face‐to‐face individualized counselling, our health care system, and to attitudes of the Finnish population, which are generally favourable towards health care and disease prevention. Int. J. Cancer (Pred. Oncol.) 89:44–50, 2000.

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing

Background: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy. Methods: In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families. Results: After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach. Conclusion: In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

Comprehension of cancer risk one and 12 months after predictive genetic testing for hereditary non-polyposis colorectal cancer

Editor—The main purpose of offering predictive genetic testing for hereditary cancer is to reduce unnecessary worry among those with a low risk of cancer (mutation negative) and to recognise those with a high risk (mutation positive), so as to promote preventive measures.1 2 Ideally, those shown to be at high risk would understand this, would learn to live with the knowledge, and, most importantly, would attend cancer surveillance programmes regularly. Those at low risk would feel relieved and no physically and emotionally uncomfortable surveillance would be needed. This result would be seriously hampered if those tested did not fully understand the meaning of the test results, which could lead to unnecessary worry or failure to adhere to surveillance. At present, most predictive tests are performed in carefully organised settings, which include comprehensive pre- and post-test counselling that would be expected to minimise the risk of misunderstanding the test result. However, commercial tests predicting cancer are already available,3 and this has raised concerns about predictive testing with minimal counselling or even without personal contact with a health care professional.1 4 The impact of genetic counselling on risk perception and impact of risk perception on genetic testing intentions has been studied previously.5 However, this is the first report on the comprehension of test results (perception of cancer risk) after predictive genetic testing for cancer, in this case hereditary non-polyposis colorectal cancer (HNPCC), which is the most common form of hereditary colon cancer. HNPCC is an autosomal dominant disease of adulthood with an 80-90% lifetime risk for colorectal cancer and a lesser risk of extracolonic cancers, the most common of which are endometrial and gastric cancer.6 Hereditary colorectal cancer differs essentially from other hereditary cancers, of which hereditary breast cancer is a good example. Firstly, in …

Life and Health Insurance Behaviour of Individuals Having Undergone a Predictive Genetic Testing Programme for Hereditary Non-Polyposis Colorectal Cancer

Objective and Methods: We describe the insurance behaviour of subjects (n = 271) who had previously taken a predictive genetic test for hereditary non-polyposis colorectal cancer (HNPCC); 31% of them were mutation positive, indicating a high risk of cancer. One year after testing, the subjects were sent a questionnaire including questions about their present life and health insurance before participation in the study, and their actual and planned purchase of the insurance policies during the testing programme which comprised a pre-test counselling session, a period for reflection, the testing, and a test disclosure session. Results: Thirty percent reported that they already had a life insurance and 14% a health insurance before participating in the study. The mutation-positive subjects possessed a health insurance significantly more often than the mutation-negative individuals (21 vs. 11%, p = 0.02) and a similar trend was observed for life insurance (36 vs. 28%, p = 0.12). Life and health insurance policies purchased just before testing was reported by 3 and 2% of the subjects, respectively. Life and health insurance policies purchased after testing were reported by 3 and <1%, respectively, and planned purchase by 3 and 2%, respectively. No statistically significant differences were found between the groups defined by mutation status in reports of life or health insurance behaviour during or after the programme. Conclusion: According to self-reported data, the mutation-positive subjects did not differ from the others in the purchase of life or health insurance policies. However, the mutation-positive individuals reported that they possessed health insurance policies before entering the study more often than their counterparts.

“I would like to discuss it further with an expert”: a focus group study of Finnish adults’ perspectives on genetic secondary findings

Lowered costs of genomic sequencing facilitate analyzing large segments of genetic data. Ethical debate has focused on whether and what kind of incidental or secondary findings (SFs) to report, and how to obtain valid informed consent. However, people’s support needs after receiving SFs have received less attention. We explored Finnish adults’ perspectives on reporting genetic SFs. In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. Major themes were immediate shock, dealing with worry and heightened risk, fear of being left alone to deal with SFs, disclosing to family, and identified support needs. Despite their willingness to receive SFs, participants were concerned about being left alone to deal with them. Empathetic expert support and timely access to preventive care were seen as essential to coping with shock and worry, and disclosing SFs to family. Discussion around SFs needs to concern not only which findings to report, but also how healthcare systems need to prepare for providing timely access to preventive care and support for individuals and families.

Lay Perspectives on Receiving Different Types of Genomic Secondary Findings: a Qualitative Vignette Study

Genome-wide sequencing may generate secondary findings (SFs). It is recommended that validated, clinically actionable SFs are reported back to patients/research participants. To explore publics’ perspectives on the best ways to do this, we performed a vignette study among Finnish adults. Our aim was to explore how lay people react to different types of hypothetical genomic SFs. Participants received a hypothetical letter revealing a SF predisposing to a severe but actionable disease—cardiovascular disease (familial hypercholesterolemia, long QT syndrome) or cancer (Lynch syndrome, Li–Fraumeni syndrome). Participants (N = 29) wrote down their initial reactions, and discussed (N = 23) these in focus groups. Data were analyzed using inductive thematic analysis. Reactions to hypothetical SFs varied according to perceived severity and familiarity of the diseases. SFs for cancer were perceived as more threatening than for cardiovascular diseases, but less distressing than risk for psychiatric or neurological disorders, which participants spontaneously brought up. Illness severity in terms of lived experience, availability of treatment, stigma, and individual’s responsibility to control risk were perceived to vary across these disease types. In addition to clinical validity and utility, SF reporting practices need to take into account potential familiarity and lay illness representations of different diseases. Illness representations may influence willingness to receive SFs, and individuals’ reactions to this information.