RESUMO
BACKGROUND: Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting. METHODS: Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records. RESULTS: In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding. CONCLUSIONS: This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.
Assuntos
Neoplasias da Mama , Síndrome Hereditária de Câncer de Mama e Ovário , Neoplasias Ovarianas , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Testes Genéticos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias de Mama Triplo Negativas/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Targeted surveillance of at-risk individuals in families with increased risk of hereditary cancer is an effective prevention strategy if relatives are identified, informed and enrolled in screening programs. Despite the potential benefits, many eligible at-risk relatives remain uninformed of their cancer risk. This study describes the general public's opinion on disclosure of hereditary colorectal cancer (CRC) risk information, as well as preferences on the source and the mode of information. METHODS: A random sample of the general public was assessed through a Swedish citizen web-panel. Respondents were presented with scenarios of being an at-risk relative in a family that had an estimated increased hereditary risk of CRC; either 10% (moderate) or 70% (high) lifetime risk. A colonoscopy was presented as a preventive measure. Results were analysed to identify significant differences between groups using the Pearson's chi-square (χ2) test. RESULTS: Of 1800 invited participants, 977 completed the survey (54%). In the moderate and high-risk scenarios, 89.2 and 90.6% respectively, would like to receive information about a potential hereditary risk of CRC (χ2, p = .755). The desire to be informed was higher among women (91.5%) than men (87.0%, χ2, p = .044). No significant differences were found when comparing different age groups, educational levels, place of residence and having children or not. The preferred source of risk information was a healthcare professional in both moderate and high-risk scenarios (80.1 and 75.5%). However, 18.1 and 20.1% respectively would prefer to be informed by a family member. Assuming that healthcare professionals disclosed the information, the favoured mode of information was letter and phone (38.4 and 33.2%). CONCLUSIONS: In this study a majority of respondents wanted to be informed about a potential hereditary risk of CRC and preferred healthcare professionals to communicate this information. The two presented levels of CRC lifetime risk did not significantly affect the interest in being informed. Our data offer insights into the needs and preferences of the Swedish population, providing a rationale for developing complementary healthcare-assisted communication pathways to realise the full potential of targeted prevention of hereditary CRC.
RESUMO
Direct contact may be an option for supporting disclosure in families with hereditary cancer risk. In this qualitative interview study, we explored how healthy at-risk relatives experience receiving a letter with information about hereditary cancer directly from healthcare rather than via a relative. The study is part of an ongoing multicentre randomised clinical trial in Sweden that evaluates the effectiveness of direct letters from cancer genetics clinics to at-risk relatives. After conducting semi-structured interviews with 14 relatives who had received a letter and contacted the clinic, we analysed the data using thematic analysis. The relatives had different levels of prior knowledge about the hereditary cancer assessment. Many had been notified by family that a letter was coming but some had not. Overall, these participants believed healthcare-mediated disclosure could complement family-mediated disclosure. They expressed that the letter and the message raised concerns and a need for counselling, and they wanted healthcare to be accessible and informed when making contact. The participants found the message easier to cope with when they had been notified by a family member beforehand, with a general attitude that notifying relatives was the appropriate step to take. They thought healthcare should help patients with the disclosure process but also guard the right of at-risk relatives to be informed. The findings support a direct approach from healthcare as a possible complement to an established model of family-mediated risk disclosure, but implementation must be made within existing frameworks of good practice for genetic counselling.
Assuntos
Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Feminino , Masculino , Aconselhamento Genético/psicologia , Pessoa de Meia-Idade , Adulto , Suécia , Neoplasias/genética , Família/psicologia , Idoso , Testes Genéticos/métodosRESUMO
BACKGROUND: The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial. METHODS: Probands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results. DISCUSSION: This paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019). Also registered at the website "RCC Cancerstudier i Sverige" as study #86719.
Assuntos
Revelação , Neoplasias , Humanos , Suécia , Testes Genéticos/métodos , Predisposição Genética para Doença , Atenção à Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
Women with BRCA variants have a high lifetime risk of developing breast and ovarian cancer. The aim of this study was to investigate the standard incidence ratios (SIR) for breast and ovarian cancer and standard mortality ratios (SMR) in a population-based cohort of women in Western Sweden, under surveillance and after risk reducing surgery. Women who tested positive for a BRCA variant between 1995-2016 (n = 489) were prospectively registered and followed up for cancer incidence, risk reducing surgery and mortality. The Swedish Cancer Register was used to compare breast and ovarian cancer incidence and mortality with and without risk reducing surgery for women with BRCA variants in comparison to women in the general population. SIR for breast cancer under surveillance until risk-reducing mastectomy (RRM) was 14.0 (95% CI 9.42-20.7) and decreased to 1.93 (95% CI 0.48-7.7) after RRM. The SIR for ovarian cancer was 124.6 (95% CI 59.4-261.3) under surveillance until risk reducing salpingo-oophorectomy (RRSO) and decreased to 13.5 (95% CI 4.34-41.8) after RRSO. The SMR under surveillance before any risk reducing surgery was 5.56 (95% 2.09-14.8) and after both RRM and RRSO 4.32 (95% CI 1.62-11.5). Women with cancer diagnoses from the pathology report after risk reducing surgery were excluded from the analyses. Risk reducing surgery reduced the incidence of breast and ovarian cancer in women with BRCA variants. However, overall mortality was significantly increased in comparison to the women in the general population and remained elevated even after risk reducing surgery. These findings warrant further research regarding additional measures for these women.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/mortalidade , Adulto , Idoso , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Incidência , Mastectomia , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Ovariectomia , Polimorfismo Genético , Sistema de Registros , Comportamento de Redução do Risco , Suécia/epidemiologia , Adulto JovemRESUMO
Paclitaxel is a frequently used anticancer drug with considerable inter-individual variability in terms of drug efficiency and toxicity. The reasons for this variability have not been fully explained. The purpose of this study was to evaluate the possible relationship between paclitaxel-induced neurotoxicity and the distribution of genetic variations with reported functional significance in the ABCB1, CYP2C8 and CYP3A4 genes that are all implicated in taxol metabolism. Women (n=36) experiencing paclitaxel-induced neurotoxicity were included in the study, and the ABCB1 G2677A/T and C3435T as well as CYP2C8(*)3 and CYP3A4(*)1b allele frequencies were determined using PCR-RFLP and DNA sequence analysis. We showed that the ABCB1 3435T allele, previously reported as a risk allele for neurotoxicity, did not correlate with the occurrence of neurotoxicity in our patient sample (Chi-square test, p=0.61). Furthermore, we showed that neither the CYP2C8(*)3 nor CYP3A4(*)1b alleles, that both lead to diminished enzyme activity, correlated with paclitaxel-induced neurotoxicity. The occurrence and variation in severity of neurotoxicity in our Swedish patient sample could therefore not be explained by the reported functional polymorphisms in the ABCB1, CYP2C8 and CYP3A4 genes.
RESUMO
OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants. DESIGN AND METHODS: Restriction fragment length polymorphism (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA. RESULTS: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c.1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G. CONCLUSIONS: We report two new DPYD gene variants, of which DPYD c.1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance.