Predictors of participation in genetic testing for hereditary breast and ovarian cancer

Up to 10% of all breast and ovarian cancers are attributable to mutations in cancer susceptibility genes. Clinical genetic testing for deleterious gene mutations that predispose to hereditary breast and ovarian cancer (HBOC) syndrome is available. Mutation carriers may benefit from following high-risk guidelines for cancer prevention and early detection; however, few studies have reported the uptake of clinical genetic testing for HBOC. This study identified predictors of HBOC genetic testing uptake among a case series of 268 women who underwent genetic counseling at The University of Texas M. D. Anderson Cancer Center from October, 1996, through July, 2000. Women completed a baseline questionnaire that measured psychosocial and demographic variables. Additional medical characteristics were obtained from the medical charts. Logistic regression modeling identified predictors of participation in HBOC genetic testing. Psychological variables were hypothesized to be the strongest predictors of testing uptake—in particular, one's readiness (intention) to have testing. Testing uptake among all women in this study was 37% (n = 99). Contrary to the hypotheses, one's actual risk of carrying a BRCA1 or BRCA2 gene mutation was the strongest predictor of testing participation (OR = 15.37, CI = 5.15, 45.86). Other predictors included religious background, greater readiness to have testing, knowledge about HBOC and genetic testing, not having female children, and adherence to breast self-exam. Among the subgroup of women who were at ≥10% risk of carrying a mutation, 51% (n = 90) had genetic testing. Consistent with the hypotheses, predictors of testing participation in the high-risk subgroup included greater readiness to have testing, knowledge, and greater self-efficacy regarding one's ability to cope with test results. Women with CES-D scores ≥16, indicating the presence of depressive symptoms, were less likely to have genetic testing. Results indicate that among women with a wide range of risk for HBOC, actual risk of carrying an HBOC-predisposing mutation may be the strongest predictor of their decision to have genetic testing. Psychological variables (e.g., distress and self-efficacy) may influence testing participation only among women at highest risk of carrying a mutation, for whom genetic testing is most likely to be informative. ^

Attitudes About Predictive MEN1 Genetic Testing in Minors

Multiple Endocrine Neoplasia type 1 (MEN1) is a hereditary cancer syndrome characterized by tumors of the endocrine system. Tumors most commonly develop in the parathyroid glands, pituitary gland, and the gastro-entero pancreatic tract. MEN1 is a highly penetrant condition and age of onset is variable. Most patients are diagnosed in early adulthood; however, rare cases of MEN1 present in early childhood. Expert consensus opinion is that predictive genetic testing should be offered at age 5 years, however there are no evidence-based studies that clearly establish that predictive genetic testing at this age would be beneficial since most symptoms do not present until later in life. This study was designed to explore attitudes about the most appropriate age for predictive genetic testing from individuals at risk of having a child with MEN1. Participants who had an MEN1 mutation were invited to complete a survey and were asked to invite their spouses to participate as well. The survey included several validated measures designed to assess participants’ attitudes about predictive testing in minors. Fifty-eight affected participants and twenty-two spouses/partners completed the survey. Most participants felt that MEN1 genetic testing was appropriate in healthy minors. Younger age and increased knowledge of MEN1 genetics and inheritance predicted genetic testing at a younger age. Additionally, participants who saw more positive than negative general outcomes from genetic testing were more likely to favor genetic testing at younger ages. Overall, participants felt genetic testing should be offered at a younger age than most adult onset conditions and most felt the appropriate time for testing was when a child could understand and participate in the testing process. Psychological concerns seemed to be the primary focus of participants who favored later ages for genetic testing, while medical benefits were more commonly cited for younger age. This exploratory study has implications for counseling patients whose children are at risk of developing MEN1 and illustrates issues that are important to patients and their spouses when considering testing in children.

Recommendations for Genetic Testing to Reduce the Incidence of Anthracycline-induced Cardiotoxicity

AIM Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process; including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor ( CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Adaptation to being at-risk for Huntington's disease and the availability of genetic testing: Application of a stress and coping model

This study examined the utility of a stress/coping model in explaining adaptation in two groups of people at-risk for Huntington's Disease (HD): those who have not approached genetic testing services (non-testees) and those who have engaged a testing service (testees). The aims were (1) to compare testees and non-testees on stress/coping variables, (2) to examine relations between adjustment and the stress/coping predictors in the two groups, and (3) to examine relations between the stress/coping variables and testees' satisfaction with their first counselling session. Participants were 44 testees and 40 non-testees who completed questionnaires which measured the stress/coping variables: adjustment (global distress, depression, health anxiety, social and dyadic adjustment), genetic testing concerns, testing context (HD contact, experience, knowledge), appraisal (control, threat, self-efficacy), coping strategies (avoidance, self-blame, wishful thinking, seeking support, problem solving), social support and locus of control. Testees also completed a genetic counselling session satisfaction scale. As expected, non-testees reported lower self-efficacy and control appraisals, higher threat and passive avoidant coping than testees. Overall, results supported the hypothesis that within each group poorer adjustment would be related to higher genetic testing concerns, contact with HD, threat appraisals, passive avoidant coping and external locus of control, and lower levels of positive experiences with HD, social support, internal locus of control, self-efficacy, control appraisals, problem solving, emotional approach and seeking social support coping. Session satisfaction scores were positively correlated with dyadic adjustment, problem solving and positive experience with HD, and inversely related to testing concerns, and threat and control appraisals. Findings support the utility of the stress/coping model in explaining adaptation in people who have decided not to seek genetic testing for HD and those who have decided to engage a genetic testing service.

Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing

Background: Women who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently. early age of onset of cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing. Design: Each of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases. Results: Our predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%. Conclusion: The inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of "serious" risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

ATTITUDES AND PRACTICES OF GENETIC COUNSELORS IN PROVIDING PREDICTIVE TESTING TO MINORS AT RISK FOR LI-FRAUMENI SYNDROME

Li- Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome caused by mutations in the TP53 gene that predisposes individuals to a wide variety of cancers, including breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, and adrenocortical carcinomas. Individuals found to carry germline mutations in TP53 have a 90% lifetime cancer risk, with a 20% chance to develop cancer under the age of 20. Despite the significant risk of childhood cancer, predictive testing for unaffected minors at risk for LFS historically has not been recommended, largely due to the lack of available and effective screening for the types of cancers involved. A recently developed screening protocol suggests an advantage to identifying and screening children at risk for LFS and we therefore hypothesized that this alongside with the availability of new screening modalities may substantiate a shift in recommendations for predictive genetic testing in minors at risk for LFS. We aimed to describe current screening recommendations that genetic counselors provide to this population as well as explore factors that may have influenced genetic counselors attitude and practice in regards to this issue. An online survey was emailed to members of the National Society of Genetic Counselors (NSGC) and the Canadian Association of Genetic Counsellors (CAGC). Of an estimated 1000 eligible participants, 172 completed surveys that were analyzed. Genetic counselors in this study were more likely to support predictive genetic testing for this population as the minor aged (p

Genetic Predictors Of Long-term Response To Growth Hormone (gh) Therapy In Children With Gh Deficiency And Turner Syndrome: The Influence Of A Socs2 Polymorphism.

There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P= .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.

Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individuals

Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus–pituitary–adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR) = 0.360, 95% confidence interval [CI]: [0.140– 0.950], p = 0.022; C3435T: OR= 0.306, 95% CI: [0.096–0.980], p = 0.042; and G2677TA: OR= 0.300, 95% CI: [0.100– 0.870], p = 0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR = 0.313, 95% CI: [0.118–0.832], p = 0.016, FDR p = 0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.

Genetic Screening of LCA in Belgium: Predominance of CEP290 and Identification of Potential Modifier Alleles in AHI1 of CEP290-Related Phenotypes

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.

Diagnostic interview for genetic studies (DIGS): inter-rater and test-retest reliability of the French version.

The National Institute of Mental Health developed the semi-structured Diagnostic Interview for Genetic Studies (DIGS) for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS was translated into French in a collaborative effort of investigators from sites in France and Switzerland. Inter-rater and test-retest reliability of the French version have been established in a clinical sample in Lausanne. Excellent inter-rater reliability was found for schizophrenia, bipolar disorder, major depression, and unipolar schizoaffective disorder while fair inter-rater reliability was demonstrated for bipolar schizoaffective disorder. Using a six-week test-retest interval, reliability for all diagnoses was found to be fair to good with the exception of bipolar schizoaffective disorder. The lower test-retest reliability was the result of a relatively long test-retest interval that favored incomplete symptom recall. In order to increase reliability for lifetime diagnoses in persons not currently affected, best-estimate procedures using additional sources of diagnostic information such as medical records and reports from relatives should supplement DIGS information in family-genetic studies. Within such a procedure, the DIGS appears to be a useful part of data collection for genetic studies on major mood disorders and schizophrenia in French-speaking populations.

Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families--performed in 12 clinical laboratories in Spain.

Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.

Les tests génétiques peuvent-ils être utiles pour la prévention cardiovasculaire? [Are genetic tests useful for cardiovascular prevention?].

Recent progresses in genetics have opened new avenues to further our understanding of the pathophysiological mechanisms underlying cardiovascular disease, raising, new expectations in the field of personalized medicine. Genetic tests may have a high predictive value for rare monogenic diseases. The situation is very different for common polygenic diseases, such as myocardial infarction, type 2 diabetes or stroke. The results from recent genome-wide association studies have provided useful information for research, but have not yet been proven to be clinically useful. It is therefore currently not recommended to conducted genetic testing to guide cardiovascular prevention neither in clinical nor in public health settings.

Deciphering genetic disease in the genomic era: the model of GnRH deficiency.

Isolated gonadotropin-releasing hormone (GnRH) deficiency is a treatable albeit rare form of reproductive failure that has revealed physiological mechanisms controlling human reproduction, but despite substantial progress in discovering pathogenic single-gene defects, most of the genetic basis of GnRH deficiency remains uncharted. Although unbiased genetic investigations of affected families have identified mutations in previously unsuspected genes as causes of this disease in some cases, their application has been severely limited because of the negative effect of GnRH deficiency on fertility; moreover, relatively few of the many candidate genes nominated because of biological plausibility from in vitro or animal model experiments were subsequently validated in patients. With the advent of exciting technological platforms for sequencing, homozygosity mapping, and detection of structural variation at the whole-genome level, human investigations are again assuming the leading role for gene discovery. Using human GnRH deficiency as a paradigm and presenting original data from the screening of numerous candidate genes, we discuss the emerging model of patient-focused clinical genetic research and its complementarities with basic approaches in the near future.