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.     

The use of genetic testing in hereditary colorectal cancer syndromes: genetic testing in HNPCC, (A)FAP and MAP

This study evaluated the use of genetic testing and time trends in hereditary non-polyposis colorectal cancer (HNPCC), (attenuated) familial adenomatous polyposis [(A)FAP] and human MutY homolog (MUTYH) associated polyposis (MAP) families. Eighty-seven families, who were diagnosed with disease-causing mutations between 1995 and 2006, were included in this study. The families consisted of 1547 individuals at risk. Data of these individuals were collected from medical records and family pedigrees. There was considerable interest in genetic testing with test rates of 41% in HNPCC families, 42% in (A)FAP families and 53% in MAP families. The use of genetic testing was associated with age and parenthood. Despite the interest in genetic testing, many risk carriers do not apply for testing. Moreover, time trend analysis showed a decline in test rate in HNPCC families. Studies evaluating the reasons for not testing are needed. Furthermore, a better implementation of genetic testing in clinical practice is desirable.     

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion. Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event. Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss.     

Development and testing of the KnowGene scale to assess general cancer genetic knowledge related to multigene panel testing

PurposeTo develop and evaluate a measure of cancer genetics knowledge relevant to multigene panel testing.MethodsThe instrument was developed using systematic input from a national panel of genetics experts, acceptability evaluation by patient advocates, and cognitive testing. Twenty-four candidate items were completed by 591 breast or gynecological patients who had undergone genetic counseling and multigene panel testing in the past 18 months. A unidimensional item response theory model was fit with a mix of 2-parameter logistic nested response (2 plnrm) and 2-parameter logistic (2 pl) items.ResultsKey domains addressing cancer genetics knowledge were found to be overlapping. Of the 24 candidate items, 8 items were removed due to poor discrimination or local dependence. The remaining 16 items had good fit (RMSEA = 0.045, CFI = 0.946) and discrimination parameters ranging from 0.49 to 1.60. The items specified as 2 plnrm distinguish between those answering incorrect versus don’t know, with discrimination ranging from 0.51 to 1.02. Information curves were highest among those with lower knowledge.ConclusionKnowGene is a rigorously developed and effective measure of knowledge after cancer genetic counseling and multigene panel testing.Practice ImplicationsMeasuring knowledge in a systematic way will inform practice and research initiatives in cancer genetics.     

Implementing digital systems to facilitate genetic testing for hereditary cancer syndromes: An observational study of 4 clinical workflows

PurposeNational efforts have prioritized the identification of effective methods for increasing case ascertainment and delivery of evidence-based health care for individuals at elevated risk for hereditary cancers.MethodsThis study examined the uptake of genetic counseling and testing following the use of a digital cancer genetic risk assessment program implemented at 27 health care sites in 10 states using 1 of 4 clinical workflows: (1) traditional referral, (2) point-of-care scheduling, (3) point-of-care counseling/telegenetics, and (4) point-of-care testing.ResultsIn 2019, 102,542 patients were screened and 33,113 (32%) were identified as at high risk and meeting National Comprehensive Cancer Network genetic testing criteria for hereditary breast and ovarian cancer, Lynch syndrome, or both. Among those identified at high risk, 5147 (16%) proceeded with genetic testing. Genetic counseling uptake was 11% among the sites with workflows that included seeing a genetic counselor before testing, with 88% of patients proceeding with genetic testing after counseling. Uptake of genetic testing across sites varied significantly by clinical workflow (6% referral, 10% point-of-care scheduling, 14% point-of-care counseling/telegenetics, and 35% point-of-care testing, P < .0001).ConclusionStudy findings highlight the potential heterogeneity of effectiveness attributable to different care delivery approaches for implementing digital hereditary cancer risk screening programs.     

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian,pancreatic, and prostate cancer

PurposeTo address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone.MethodsAmong 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model.ResultsOnly 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (p_Time < 0.001; p_Time2 < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty.ConclusionThis mainstreaming model may offer a feasible approach for extending access to germline genetic information.     

Familial testicular cancer: interest in genetic testing among high-risk family members.

PURPOSE: This study is part of an ongoing National Cancer Institute multidisciplinary, etiologically-focused, cross-sectional study of Familial Testicular Cancer (FTC). The current report targets interest in clinical genetic testing for susceptibility to FTC. METHODS: Demographics, knowledge, health beliefs, and psychological and social factors were evaluated as covariates related to interest in genetic testing. RESULTS: The majority (66%) of 229 participants (64 affected men, 66 unaffected men, and 99 women) from 47 multiple-case FTC families expressed interest in having a genetic test within 6 months, should such a test become available. Interest was similar among the three subgroups mentioned above. Worries about insurance discrimination based on genetic test results were associated with a significantly lower interest in testing. Alternatively, participants were more likely to be interested in genetic testing if they were younger and had higher levels of family support, a physician's recommendation supporting testing, cancer distress, and a need for information to inform the health care of their children. CONCLUSIONS: This study reveals social and relationship factors that FTC survivors and their relatives considered important when contemplating the use of new genetic technologies. This is the first study describing hypothetical interest in genetic testing for familial testicular cancer.     

Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort

PurposeGenetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants.MethodsWe analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions.ResultsTwenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign.ConclusionThe evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.     

Perceptions of genetic testing in patients with hereditary chronic pancreatitis and their families: a qualitative triangulation

Hereditary chronic pancreatitis (HCP) is a genetically determined condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of the exocrine and endocrine pancreatic functions. Genetic test results can have substantial psychological and social consequences for the individuals tested and their families. Nevertheless, little is known so far about the subjective experience of individuals genetically tested for HCP. This qualitative study examines the viewpoints of HCP patients and their relatives in order to identify the psychosocial and ethical implications related to genetic testing within families. Semi-structured qualitative individual interviews and a focus group with HCP patients and their family members were conducted. Data were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. A total of 28 individuals were enrolled in the study: 24 individuals (17 patients, 7 relatives) were interviewed in semi-structured one-on-one interviews and 4 individuals (2 patients, 2 life partners) participated in the focus group. Emerging topics covered (1) genetic testing in childhood, (2) genetic testing within the family and (3) family planning. The study reveals that genetic testing for HCP has a wide influence in familial contexts and is accompanied by normative issues, such as autonomy, reproductive decisions and sharing of information within the family. The results raise the awareness of the complexity of family contexts: familial relationships and dynamics can have great influence on the individual decisions related to genetic testing. Increased understanding of these relational contexts can help health professionals, for example, in counselling, to discuss genetic testing better with patients and families.Subject terms: Medical ethics, Quality of life, Health services, Ethics, Psychology     

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications.

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.     

Communication with close and distant relatives in the context of genetic testing for hereditary breast and ovarian cancer in cancer patients

The psychological aspects of genetic testing for hereditary breast and ovarian cancer (HBOC) in cancer patients (diagnostic genetic testing) have so far received less attention than predictive genetic testing in unaffected persons. Our study is aimed at gaining insight into the psychological aspects of diagnostic genetic testing and at formulating practical recommendations for counseling. Cancer patients often play a key role in the communication of information to relatives because they were the first individuals to be tested in the family. The present article focuses on the communication to close and distant relatives about the hereditary cancer, the genetic test and its result. Participants previously diagnosed with breast and/or ovarian cancer, with a family history of these cancers and who requested DNA-testing, were eligible for the study. Of the 83 eligible patients who could be contacted, 63 participated (response rate = 76%). Twenty-six participants were members of a family where a BRCA1 or BRCA2 mutation was detected. The DNA-analysis in the family of 37 participants had not revealed any mutation. Data were collected by semi-structured interviews and psychological tests and questionnaires. The dissemination of information was largely focused on first-degree relatives. Communication to distant relatives about the genetic test and its result was problematic. Other than the genetic test result and age as "objective" predictors of informing distant relatives, little and/or superficial contact seemed to be the major subjective barrier to informing distant relatives. Furthermore, the knowledge about HBOC of these messengers reveals several shortcomings. Communication within the family should receive special attention during counseling.     

Evaluation of a counselling protocol for predictive genetic testing for hereditary non-polyposis colorectal cancer

OBJECTIVES—To evaluate the feasibility of a reduced counselling programme for predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) in terms of counsellees' opinions on the extent and significance of genetic counselling and need for psychological support at different phases of the testing procedure.
DESIGN—Prospective follow up study with pre-test questionnaire assessment of background sociodemographic variables. The protocol comprised a pre-test counselling session, a period for reflection, and a test disclosure session. The outcome variables were studied by post-test questionnaires at one month and one year follow up.
SUBJECTS—Two hundred and seventy one high risk members of 36 families with HNPCC who attended both counselling sessions and completed the questionnaires.
RESULTS—The pre-test counselling was considered fairly or very useful by 89% of respondents and one post-test session was considered sufficient by over 80% of respondents at follow up. Fifty three percent would have used extra psychological support had it been offered with the counselling. On enquiry one year after receiving the test result, only 2% stated that the need for support was at its greatest at that time, while the majority (46%) reported that the need for support had been greatest at the moment of test disclosure.
CONCLUSIONS—A protocol that includes one comprehensive pre-test counselling session and a test disclosure session, supplemented with the option of professional psychological support, seems to be sufficient for both the educational and supportive needs of counsellees. Only a minority expressed a need for post-test follow up sessions, which suggests that, in this disorder, resources can be directed to the beneficial surveillance programmes rather than to extensive psychological support.


Keywords: predictive genetic testing; genetic counselling; HNPCC; hereditary non-polyposis colorectal cancer     

The impact of predictive genetic testing for hereditary nonpolyposis colorectal cancer: three years after testing.

BACKGROUND: To fully assess predictive genetic testing programs, it is important to assess outcomes over periods of time longer than the 1-year follow-up reported in the literature. METHODS: We conducted a 3-year study of individuals who received predictive genetic test results for previously identified familial mutations in Australian Familial Cancer Clinics. Questionnaires were sent before attendance at the familial cancer clinic and 2 weeks, 4 months, 1 year, and 3 years after receiving test results. Psychological measures were included each time, and preventive behaviors were assessed at baseline and 1 and 3 years. Psychological measures were adjusted for age, gender, and baseline score. RESULTS: The study included 19 carriers and 54 non-carriers. We previously reported an increase in mean cancer-specific distress in carriers at 2 weeks with a return to baseline levels by 12 months. This level was maintained until 3 years. Non-carriers showed sustained decreases after testing with a significantly lower level at 3 years compared with baseline (P < 0.001). These scores tended to be lower than those for carriers at 3 years (P = 0.09). Mean depression and anxiety scores did not differ between carriers and non-carriers and, at 3 years, were similar to baseline. All carriers and 7% of non-carriers had had a colonoscopy by 3 years, and 69% of 13 female carriers had undergone gynecological screening in the previous 2 years. Prophylactic surgery was rare. CONCLUSION: This report of long-term data indicates appropriate screening and improved psychological measures for non-carriers with no evidence of undue psychological distress in carriers of hereditary nonpolyposis colorectal cancer mutations.     

Attitudes about genetic testing and genetic testing intentions in African American women at increased risk for hereditary breast cancer.

PURPOSE: To evaluate attitudes about the benefits, limitations, and risks of genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and explore testing intentions in African American women at increased risk for hereditary breast cancer. METHODS: Attitudes and intentions were evaluated by telephone in African American women (n = 74) at moderate and high risk for having a BRCA1/2 mutation. RESULTS: Attitudes about the benefits of genetic testing were endorsed at a higher rate relative to limitations and risks; however, only 30% of respondents indicated that they would definitely have testing. In regression analysis, women most likely to be considering testing were those with fatalistic beliefs about cancer and those who believed they had a BRCA1/2 mutation. Women who had two or more affected relatives were also most likely to be considering testing. Women who had a personal history of cancer and those who believed they were at high risk for developing breast cancer were most likely to report greater limitations and risks. Pros scores were higher among women older than age 50 and those who were unemployed. CONCLUSION: Although African American women at moderate and high risk for BRCA1/2 mutations report favorable attitudes about genetic testing, interest in testing may be limited. Women affected with cancer and those who believe they are at a higher risk for developing breast cancer may be most concerned about the negative consequences of testing. Increased attention may need to be given to beliefs about genetic testing and testing motivations during genetic counseling with African American women.