Update Swiss guideline for counselling and testing for predisposition to breast, ovarian, pancreatic and prostate cancer.

This paper presents the Swiss guideline for genetic counselling and testing of individuals with an increased probability for carrying mutations in high risk cancer predisposition genes, particularly BRCA1 and BRCA2. It aims to help providers of genetic counselling to identify valuable candidates for testing and serves as a basis for reimbursement claims to Swiss insurance companies.

Key messages for communicating information about BRCA1 and BRCA2 to women with breast or ovarian cancer: Consensus across health professionals and service users.

BACKGROUND: Genetic testing of cancer predisposing genes will increasingly be needed in oncology clinics to target cancer treatment. This Delphi study aimed to identify areas of agreement and disagreement between genetics and oncology health professionals and service users about the key messages required by women with breast/ovarian cancer who undergo BRCA1/BRCA2 genetic testing and the optimal timing of communicating key messages. METHODS: Participants were 16 expert health professionals specialising in oncology/genetics and 16 service users with breast/ovarian cancer and a pathogenic BRCA1/BRCA2 variant. Online questionnaires containing 53 inductively developed information messages were circulated to the groups separately. Participants rated each message as key/not key on a Likert scale and suggested additional messages. Questionnaires were modified according to the feedback and up to 3 rounds were circulated. Consensus was reached when there was ≥75% agreement. RESULTS: Thirty key messages were agreed by both groups with 7 of the key messages agreed by ≥95% of participants: dominant inheritance, the availability of predictive testing, the importance of pretest discussion, increased risk of breast and ovarian cancer, and the option of risk-reducing mastectomy and bilateral salpingo-oophorectomy. Both groups agreed that key messages should be communicated before genetic testing and once a pathogenic variant has been identified. CONCLUSIONS: There was a high level of agreement within and between the groups about the information requirements of women with breast/ovarian cancer about BRCA1/BRCA2. These key messages will be helpful in developing new approaches to the delivery of information as genetic testing becomes further integrated into mainstream oncology services.

Genetic Testing for Rare Cancer: The Wider Issues.

Identification of a potential genetic susceptibility to cancer and confirmation of a pathogenic gene mutation raises a number of challenging issues for the patient with cancer, their relatives and the health professionals caring for them. The specific risks and management issues associated with rare cancer types have been addressed in the earlier chapters. This chapter considers the wider issues involved in genetic counselling and genetic testing for a genetic susceptibility to cancer for patients, families and health professionals. The first part of the chapter will present the issues raised by the current practice in genetic counselling and genetic testing for cancer susceptibility. The second part of the chapter will address some of the issues raised by the advances in genetic testing technology and the future opportunities provided by personalised medicine and targeted cancer therapy. Facilitating these developments requires closer integration of genomics into mainstream cancer care, challenging the existing paradigm of genetic medicine, adding additional layers of complexity to the risk assessment and management of cancer and presenting wider issues for patients, families, health professionals and clinical services.

Birt-Hogg-Dubé syndrome with a renal angiomyolipoma: further evidence of a relationship between Birt-Hogg-Dubé syndrome and tuberous sclerosis complex.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant condition caused by mutations in the gene which codes for folliculin (FLCN). It is characterised clinically by fibrofolliculomas, trichodiscomas, pulmonary cysts, spontaneous pneumothoraces and renal cancers. This case illustrates a patient with BHDS and a renal angiomyolipoma. Angiomyolipomas are not described as a feature of BHDS, but rather they can occur sporadically or in tuberous sclerosis complex (TSC). Recent studies suggest that clinical similarities between BHDS and TSC may be explained by FLCN and TSC proteins functioning on a common pathway, mammalian target of rapamycin. This case adds to the literature of cases with clinical similarities.

Novel one-stop multidisciplinary follow-up clinic for BRCA1/2 carriers: patient satisfaction and decision making.

OBJECTIVE: To evaluate patient' satisfaction and cancer risk management decision making, following attendance at a novel multidisciplinary one-stop follow-up clinic (MDOSC) for BRCA1/2 carriers. PATIENTS AND METHODS: 172 patients attended the MDOSC over a 2-year period between 2006 and 2008. A total of 96 and 76 patients were seen in the first and second year, respectively. All patients who attended the MDOSC were sent a 17-item Satisfaction Questionnaire (SQ) designed to examine their views about the MDOSC, using rating scales and open questions after the first year. Patients were asked to comment on the most helpful aspects of the MDOSC and on how the service might be improved. Changes were made based on this feedback. During the second year, all patients were given the SQ with three questions about cancer risk management decision making on the day of the MDOSC. RESULTS: In total, 132 (77%) patients responded and overall satisfaction was high with a mean of 8.94 (range 1-10). BRCA1/2 carriers were pleased to see a range of health care professionals on the same day, who they viewed gave consistent information, considered every aspect of care and addressed psychosocial needs. Following improvements, based on patients' feedback, satisfaction significantly increased in year 2. Furthermore, the MDOSC also helped patients to move forward with their cancer risk management decisions. CONCLUSIONS: BRCA1/2 carriers were highly satisfied with the MDOSC, which met their needs and helped them to make informed decisions regarding their cancer risk management.

Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1.

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.

Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues?

OBJECTIVE: To calculate and discuss the percentage of imbalance for selected cancer predisposition genes in patients referred for routine diagnostic array comparative genomic hybridisation (CGH). DESIGN: Audit of findings from application of array CGH for patients referred for developmental delay, behavioural abnormalities and birth defects in 4805 patients referred to Guy's and St Thomas' NHS Foundation Trust for cytogenetic investigation from South East London, Kent and East Sussex and other genetic centres across the UK. RESULTS: 29 of 4805 (0.6%) patients examined by array CGH had genomic imbalance of <5 Mb involving cancer predisposition genes. Six patients were referred for syndromes involving cancer predisposition genes; none of the other 23 patients with array CGH findings in cancer predisposition genes had any symptoms/family history stated on their referral form suggestive for the respective syndrome. Twelve whole gene deletions, two partial deletions, 12 duplications, two partial duplications, and one mosaic duplication were observed. In 17/29 patients (59%), inheritance could not be established, eight imbalances were de novo, and four inherited. CONCLUSIONS: This new technology raises the possibility of unexpected findings in cancer predisposition genes. Therefore, the possibility of such findings has to be addressed in pre-test and post-test counselling by genetically trained healthcare professionals. As many of these findings have not been described previously, their clinical significance is unknown and patients need long-term follow-up to determine their clinical relevance. This will enable genetic healthcare professionals to advise such people about their cancer risks and appropriate cancer risk management options.

Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.

CONTEXT: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE: To estimate risk and mortality reduction stratified by mutation and prior cancer status. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. MAIN OUTCOMES MEASURES: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. RESULTS: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). CONCLUSIONS: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers.

Risk-reducing salpingo-oophorectomy (RRSO) is widely used for cancer risk reduction in BRCA1 or BRCA2 (BRCA1/2) mutation carriers. Occult ovarian/fallopian tube cancers (OOC) detected at the time of RRSO have been reported in several studies with wide variability in reported prevalence. We estimated the prevalence of OOC in a prospective cohort of 647 BRCA1/2 mutation carriers from 18 centers (PROSE consortium) who underwent RRSO between 2001 and 2008. OOC was detected in 16 of 647 women (2.5%). The mean age at RRSO was 51.7 in those with OOC versus 46.6 in those without OOC (P = 0.017). Twelve of the 16 OOCs (75%) were diagnosed in women with BRCA1 mutations. Thirty-eight percent of women with OOC had stage 1 cancer versus none of the women in the PROSE database diagnosed with ovarian cancer outside of screening. Among 385 women (60%) in whom pathology reports were available for central review, 246 (64%) RRSOs were performed at participating PROSE centers while 139 (36%) were performed at local sites. Ovarian and fallopian tube tissues removed at major genetics referral centers were significantly more likely to have been examined in toto compared to specimens obtained at non-referral centers (75% vs. 30%, P < 0.001). Our results confirm that OOC may be found at the time of RRSO in BRCA1/2 mutation carriers and suggest that OOC are of a more favorable stage than cancers found outside RRSO. An unacceptably high proportion of pathologic examinations did not adequately examine ovaries and fallopian tubes obtained at RRSO.

Cutaneous signs are important in the diagnosis of the rare neoplasia syndrome Carney complex.

We describe a 15-year-old boy who presented with a stroke. Brain MRI imaging showed thalamic and multiple cerebral infarcts. An echocardiogram revealed multiple atrial masses, which were resected. Histological examination confirmed multiple atrial myxomas. Further clinical examination of the patient revealed subtle buccal and peri-oral lentigenes. The diagnosis of Carney complex was made clinically. The patient was subsequently diagnosed with testicular seminomas and a cutaneous angiomyxoma. Genetic investigation revealed a pathological mutation in the PRKAR1A gene. We review the reported manifestations and presentations of Carney complex, along with current diagnostic guidelines. We emphasise the importance of recognising the cutaneous manifestations of this rare autosomal dominantly inherited neoplasia syndrome.

No evidence that GATA3 rs570613 SNP modifies breast cancer risk.

GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR(per-allele) = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (OR(per-allele) = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RR(per-allele) = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RR(per-allele) = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.

[Genetic counseling in familial breast cancer]. / Genetische Beratung beim familiären Mammakarzinom.

It is currently estimated that 25-30% of all breast cancers have a familial background. The breast cancer lifetime risk of first degree relatives with a family history of breast cancer may be classified as slightly, moderately or highly increased above the population risk. Individuals from families with a highly increased risk for breast cancer should be offered genetic counselling and testing. Here, the elements of genetic counselling and testing and the management of families with a highly increased breast and ovarian risk will be discussed.

Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder?

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith Disease, is a rare cancer-associated genodermatosis with an autosomal dominant inheritance. Affected patients suffer from recurrent skin lesions, which clinically and histologically resemble keratoacanthomas or well-differentiated squamous cell carcinomas, but which, if left, undergo spontaneous regression, leaving pronounced scarring. The majority of MSSE cases previously described were of Scottish ancestry and all shared the same at-risk haplotype, suggesting that this disorder was caused by a founder mutation. The candidate locus for MSSE lies in a region of <4 cM in chromosome 9q22, between the markers D9S197 and D9S1809. We recently investigated MSSE families of non-Scottish origin. For every patient of these families, we obtained a detailed clinical history, with particular attention to the age of onset, distribution, and clinical course of their skin lesions. Once confirmed that they were really affected by MSSE, we performed haplotype analysis on them and their families. The haplotypes for polymorphic markers segregating with MSSE in non-Scottish and Scottish families differ, suggesting that MSSE is not caused by a founder mutation and might be more common than originally thought.

Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls.

INTRODUCTION: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk. METHODS: The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-beta, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid. RESULTS: Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls (p = 0.13). CONCLUSION: We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers.

Loss of heterozygosity at the BRCA1 and BRCA2 loci detected in ductal lavage fluid from BRCA gene mutation carriers and controls.

Female BRCA gene mutation carriers are at increased risk for developing breast cancer. Ductal lavage is a novel method for sampling breast ductal fluid, providing epithelial cells for cytologic assessment and a source of free DNA for molecular analyses. Loss of heterozygosity (LOH) at the BRCA loci in ductal lavage fluid is a potential biomarker of breast cancer risk. The LOH rate was measured at the BRCA1/2 loci and compared with that at a control locus (APC) using free DNA from the ductal lavage fluid of BRCA carriers and predictive test negative controls. We evaluated the reproducibility of these analyses. Free DNA sufficient for PCR amplification was obtained from 33 ductal lavage samples of 17 healthy women of known BRCA status (14 BRCA carriers and 3 controls). LOH rates of 36.4% to 56.3% at the BRCA1 locus and 45% to 61.5% at the BRCA2 locus were found among BRCA carriers. The LOH rate at the APC locus was lower (18.5%). The interaliquot reproducibility for the D17S855 marker of the BRCA1 locus was 66.7%. Intraaliquot reproducibility was 90%. Although we successfully isolated sufficient free DNA from ductal lavage fluid for PCR amplification, the degree of reproducibility of these LOH studies raises questions about the robustness of this technique as a risk assessment tool in the evaluation of high-risk women. Further studies are required to evaluate the specificity and predictive value of LOH in ductal lavage fluid for breast cancer development.

Familial non-BRCA1/BRCA2-associated breast cancer.

Multidisciplinary breast-cancer teams commonly encounter women, both premenopausal and postmenopausal, presenting with breast cancer who also have a family history of this disease. Much of the published work on management of hereditary breast cancer focuses on women with known mutations in BRCA1 and BRCA2, in whom high-grade tumours, common second primaries, and a differential response to adjuvant chemotherapies could be relevant in finding the most effective management strategies. Extrapolation of some of these findings to all patients with familial breast cancer is tempting. However, for women in whom BRCA1 or BRCA2 mutations are unlikely or not found, what evidence is there to inform choices about the various management options? We review the published work on management issues for patients with familial breast cancer not due to a detectable mutation in BRCA1/BRCA2 and compare it with the issues for BRCA1 and BRCA2 carriers on whom more information is available.

Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international Federation of gynecology and obstetrics system.

PURPOSE: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA-125 estimation) in detecting presymptomatic ovarian cancer in women at increased genetic risk. PATIENTS AND METHODS: A cohort of 1,110 women at increased risk of ovarian cancer were screened between January 1991 and March 2004; 553 were moderate-risk individuals (4% to 10% lifetime risk) and 557 were high-risk individuals (> 10% lifetime risk). Outcome measurements include the number and stage of screen-detected cancers, the number and stage of cancers not detected at screening, the number of equivocal screening results requiring recall/repetition, and the number of women undergoing surgery for benign disease. RESULTS: Thirteen epithelial ovarian malignancies (12 invasive and one borderline), developed in the cohort. Ten tumors were detected at screening: three International Federation of Gynecology and Obstetrics (FIGO) stage I (including borderline), two stage II, four stage III, and one stage IV. Of the three cancers not detected by screening, two were stage III and one was stage IV; 29 women underwent diagnostic surgery but were found not to have ovarian cancer. CONCLUSION: Annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis. With a positive predictive value of 17% and a sensitivity of less than 50%, the performance of ultrasound does not satisfy the WHO screening standards. In addition, the combined protocol has a particularly high false-positive rate in premenopausal women, leading to unnecessary surgical intervention.

Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK).

PURPOSE: To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL). PATIENTS AND METHODS: After induction treatment with the standard schedule (375 mg/m2 weekly x 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B). RESULTS: The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction-negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity. CONCLUSION: Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.

Harnessing the potential of cancer genetics in healthcare.

The advancement of knowledge in genetics will have a profound effect on prediction, prevention, and treatment of cancer. It has the potential to offer more personalised healthcare that accords with an individual's genetic profile. However, the complex medical, ethical, legal, and psychosocial issues brought by our ability to test healthy individuals for cancer predisposition and the fast pace of advances in genetics pose great challenges to the medical community. Individuals and families are unlikely to benefit from an effective and ethical application of new genetic knowledge unless high quality cancer-genetics services are developed and integrated into mainstream healthcare, more research is undertaken into the prevention, causes, and treatment of cancer, and further efforts are made to improve public understanding and acceptance of cancer genetics.