IMPORTANCE: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. OBJECTIVES: To estimate age-specific risks of breast, ovarian, and ...contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. EXPOSURES: BRCA1/2 mutations, family cancer history, and mutation location. MAIN OUTCOMES AND MEASURES: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. RESULTS: Among 3886 women (median age, 38 years; interquartile range IQR, 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio HR for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). CONCLUSIONS AND RELEVANCE: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.
To estimate relative and ...absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.
This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).
Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.
Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval CI 2.99–6.61) and absolute PCa risk of 27% (95% CI 17–41%) and 60% (95% CI 43–78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43–3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68–7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99–2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07–5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14–0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20–8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24–7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44–10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.
The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.
In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.
Male BRCA2 mutation carriers have a high risk of developing prostate cancer, particularly high-grade disease. However, the risk is heterogeneous and varies with family history and the location of the mutation within the gene. BRCA1 mutations may have a similar but weaker association.
Germline pathogenic variants (GPVs) in the cancer predisposition genes
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are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines ...around clinical management of cancer risk in patients with GPV in
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, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in
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, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of
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as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of
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carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.
DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision ...repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20-150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit ...module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.
Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. ...We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
Objectives To report the long‐term outcomes from a longitudinal psychosocial study that forms part of the ‘Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening ...in men at higher genetic risk and controls’ (IMPACT) study. The IMPACT study is a multi‐national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 ( BRCA1 ) or the BReast CAncer gene 2 ( BRCA2 ). Subjects and Methods Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36‐item Short‐Form Health Survey, Memorial Anxiety Scale for PrCa , Cancer Worry Scale, risk perception and knowledge. Results A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1 , 265 with GPV in BRCA2 and 288 controls (non‐carriers from families with a known GPV ). We found no evidence of clinically concerning levels of general or cancer‐specific distress or poor health‐related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate‐specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety ( P = 0.01) and PSA ‐specific anxiety ( P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. Conclusion This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA ‐based screening programme does not have an adverse impact on psychosocial health or health‐related quality of life in these higher‐risk individuals. These results are important as more PrCa screening is targeted to higher‐risk groups.
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