Publications by authors named "Julian Barwell"

53 Publications

Letter comments on: Mainstreaming informed consent for genomic sequencing: A call for action: A single-centre comparison of mainstreamed genetic testing with a specialist genetics service - Focus on consent discussions.

Eur J Cancer 2021 Sep 13;155:307-309. Epub 2021 Aug 13.

University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, United Kingdom; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.

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http://dx.doi.org/10.1016/j.ejca.2021.06.040DOI Listing
September 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

Familial hypereosinophilia associated with eosinophilic gastrointestinal symptoms in individuals with a missense mutation in CKLF-like MARVEL transmembrane domain containing 3.

Clin Exp Allergy 2021 May 28. Epub 2021 May 28.

Institute for Lung Health, Department of Respiratory Sciences, Leicester Respiratory Biomedical Research Centre, University of Leicester and National Institute for Health Research, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK.

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http://dx.doi.org/10.1111/cea.13957DOI Listing
May 2021

Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in Carriers.

Life (Basel) 2020 Oct 31;10(11). Epub 2020 Oct 31.

Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.

Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in carriers compared to carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither or children had consistently shorter or longer telomeres than their MMR parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with mutations, had significantly longer XpYp telomeres than their MMR parent. Altogether our data suggest that MMR insufficiency, particularly in carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.
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http://dx.doi.org/10.3390/life10110265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692680PMC
October 2020

Prostate Cancer Risk by BRCA2 Genomic Regions.

Eur Urol 2020 10 10;78(4):494-497. Epub 2020 Jun 10.

Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.
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http://dx.doi.org/10.1016/j.eururo.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532700PMC
October 2020

Cancer Risks Associated With Germline Pathogenic Variants: An International Study of 524 Families.

J Clin Oncol 2020 03 16;38(7):674-685. Epub 2019 Dec 16.

Biopathologie, Centre Léon Bérard, Lyon, France.

Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline pathogenic variants (PVs) because these risks have not been extensively characterized.

Methods: We analyzed data from 524 families with PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

Results: We found associations between PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; = 6.5 × 10), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; = 4.1 × 10), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; = 8.7 × 10), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; = 2.6 × 10). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( for trend = 2.0 × 10). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

Conclusion: These results confirm as a major breast cancer susceptibility gene and establish substantial associations between germline PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of into risk prediction models and optimize the clinical cancer risk management of PV carriers.
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http://dx.doi.org/10.1200/JCO.19.01907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049229PMC
March 2020

Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic mutation carriers: a case-controlled study (SIGNIFY).

J Med Genet 2020 04 12;57(4):226-236. Epub 2019 Nov 12.

Department of Diagnostic Radiology, The Royal Marsden NHS Foundation Trust, London, UK.

Background: Germline gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.

Methods: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up.

Results: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.

Conclusion: WB-MRI screening can be implemented in pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
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http://dx.doi.org/10.1136/jmedgenet-2019-106407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146942PMC
April 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Eur Urol 2019 12 16;76(6):831-842. Epub 2019 Sep 16.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

Design, Setting, And Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.

Outcome Measurements And Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.

Results And Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).

Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.

Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
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http://dx.doi.org/10.1016/j.eururo.2019.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880781PMC
December 2019

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

Eur Urol 2020 01 6;77(1):24-35. Epub 2019 Sep 6.

Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.

Background: 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.

Objective: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.

Design, Setting, And Participants: 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).

Outcome Measurements And Statistical Analysis: 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.

Results And Limitations: 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.

Conclusions: 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.

Patient Summary: 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.
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http://dx.doi.org/10.1016/j.eururo.2019.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926480PMC
January 2020

The new genomic medicine service and implications for patients .

Clin Med (Lond) 2019 07;19(4):273-277

NHS Greater Glasgow and Clyde, Glasgow, UK.

In January 2019, a new nationally commissioned Genomic Medicine Service (GMS) has now commenced in the NHS. Capitalising on the infrastructure developed through the 100,000 Genomes Project, the GMS is underpinned by seven supra-regional Genomic Laboratory Hubs (GLHs) delivering the new inherited rare disease and cancer somatic tissue genetic test directory. This replaces the UKGTN test directory, with the aim of standardising criteria for whole genome sequencing or targeted panel tests where applicable. The new test directory will define who can order specific genetic tests under prescribed eligibility criteria. In keeping with Dame Sally Davies' white paper Generation Genome, this will further democratise genetic testing and, in some situations, avoid the need to refer to clinical genetics to access testing. The aim is to simplify patient pathways and reduce regional or social inequalities. We will discuss the implications of whole genome sequencing and the potential impact of the new nationally commissioned GMS for both patients, their relatives and clinicians. We will also discuss the imminent challenges in implementing genomic medicine into the NHS, and the future impact of novel technologies on service delivery as genomic medicine becomes increasingly integrated into routine healthcare.
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http://dx.doi.org/10.7861/clinmedicine.19-4-273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752257PMC
July 2019

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Br J Cancer 2019 07 19;121(2):180-192. Epub 2019 Jun 19.

Department of Gynaecological Oncology, Chris O'Brien Lifehouse and The University of Sydney, Camperdown, NSW, Australia.

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.

Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.

Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P < 0.05).

Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
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http://dx.doi.org/10.1038/s41416-019-0492-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738050PMC
July 2019

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

J Natl Cancer Inst 2019 04;111(4):350-364

Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT.

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.
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http://dx.doi.org/10.1093/jnci/djy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449171PMC
April 2019

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Am J Hum Genet 2018 07 14;103(1):3-18. Epub 2018 Jun 14.

North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037202PMC
July 2018

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

BJU Int 2019 02 22;123(2):284-292. Epub 2018 Jun 22.

Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objectives: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes.

Particpants And Methods: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented.

Results: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status.

Conclusion: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.
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http://dx.doi.org/10.1111/bju.14412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378691PMC
February 2019

A response to the Chief Medical Officer's report on Genomic Medicine: a catalyst for transformation.

Per Med 2018 01;15(1):5-8

University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

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http://dx.doi.org/10.2217/pme-2017-0058DOI Listing
January 2018

Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study.

Genet Med 2018 12 22;20(12):1575-1582. Epub 2018 Mar 22.

Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.

Purpose: BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives.

Methods: We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs).

Results: A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort.

Conclusion: Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.
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http://dx.doi.org/10.1038/gim.2018.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314PMC
December 2018

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Br J Cancer 2018 01 4;118(2):266-276. Epub 2018 Jan 4.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.

Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.

Results: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.

Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.
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http://dx.doi.org/10.1038/bjc.2017.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785754PMC
January 2018

Inclusion of diverse populations in genomic research and health services: Genomix workshop report.

J Community Genet 2017 Oct 28;8(4):267-273. Epub 2017 Jul 28.

Division of Primary Care, University of Nottingham, 13th Floor, Tower Building, University Park, Nottingham, NG7 2RD, UK.

Clinical genetic services and genomic research are rapidly developing but, historically, those with the greatest need are the least to benefit from these advances. This encompasses low-income communities, including those from ethnic minority and indigenous backgrounds. The "Genomix" workshop at the European Society of Human Genetics (ESHG) 2016 conference offered the opportunity to consider possible solutions for these disparities from the experiences of researchers and genetic healthcare practitioners working with underserved communities in the USA, UK and Australia. Evident from the workshop and corresponding literature is that a multi-faceted approach to engaging communities is essential. This needs to be complemented by redesigning healthcare systems that improves access and raises awareness of the needs of these communities. At a more strategic level, institutions involved in funding research, commissioning and redesigning genetic health services also need to be adequately represented by underserved populations with intrinsic mechanisms to disseminate good practice and monitor participation. Further, as genomic medicine is mainstreamed, educational programmes developed for clinicians should incorporate approaches to alleviate disparities in accessing genetic services and improving study participation.
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http://dx.doi.org/10.1007/s12687-017-0317-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614885PMC
October 2017

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

Fam Cancer 2017 07;16(3):433-440

The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, London, UK.

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.
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http://dx.doi.org/10.1007/s10689-017-9965-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487773PMC
July 2017

Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with high specificity patients with prostate cancer.

BJU Int 2016 Apr 29;117(4):686-96. Epub 2015 Jul 29.

Department of Genetics, University of Leicester, Leicester, UK.

Objectives: To evaluate the immunocytochemical detection of ERG protein in exfoliated cells as a means of identifying patients with prostate cancer (PCa) before prostate biopsy.

Materials And Methods: Urine samples (30 mL) were collected after digital rectal examination (DRE) from 159 patients with an elevated age-specific prostate-specific antigen (PSA) and/or an abnormal DRE who underwent prostate biopsy. In all cases, exfoliated urinary cells from half of the urine sample underwent immunocytochemical assessment for ERG protein expression. Exfoliated cells in the remaining half underwent assessment of TMPRSS2:ERG status using either nested reverse-transcriptase (RT)-PCR (151 cases) or fluorescence in situ hybridization (FISH; eight cases). Corresponding tissue samples were evaluated using FISH to determine chromosomal gene fusion tissue status and immunohistochemistry (IHC) to determine ERG protein expression. Results were correlated with clinicopathological variables.

Results: The sensitivity and specificity of urinary ERG immunocytochemistry (ICC) for PCa were 22.7 and 100%, respectively. ERG ICC results correlated with advanced tumour grade, stage and higher serum PSA. In comparison, urine TMPRSS2:ERG transcript analysis had 27% sensitivity and 98% specificity for PCa detection. On tissue IHC, ERG staining was highly specific for PCa. In all, 52% of cancers harboured foci of ERG staining; however, only 46% of cancers that were found to have ERG overexpression were positive on urine ICC. The ERG ICC results showed strong concordance with urinary RT-PCR and FISH, and tissue IHC and FISH.

Conclusion: This is the first study to show that cytological gene fusion detection using ICC is feasible and identifies patients with adverse disease markers. ERG ICC was highly specific, but this technique was less sensitive than RT-PCR.
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http://dx.doi.org/10.1111/bju.13184DOI Listing
April 2016

Cowden's syndrome with immunodeficiency.

J Med Genet 2015 Dec 5;52(12):856-9. Epub 2015 Aug 5.

Department of Genetics, Leicester Royal Infirmary, Leicester, UK.

Background: Cowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only.

Methods And Results: Two patients with Cowden's syndrome and an increased frequency of infections were investigated for possible underlying immunodeficiency. In one patient, hypogammaglobulinaemia with a functional antibody deficiency was identified, while the other patient had a persisting CD4+ T cell lymphopenia (with normal antibody production).

Conclusions: Our data indicate that Cowden's syndrome may be associated with both T cell and B cell immune dysfunction. We recommend that patients with Cowden's syndrome and an increased frequency of infections are investigated for associated immunodeficiency.
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http://dx.doi.org/10.1136/jmedgenet-2015-103266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661225PMC
December 2015

Supporting families with Cancer: A patient centred survivorship model of care.

Fam Cancer 2015 Dec;14(4):637-40

Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK.

In 2011, the Leicestershire Clinical Genetics Department in collaboration with Macmillan Cancer Support initiated a project called Supporting Families with Cancer (SFWC). The project aimed to raise awareness of inherited cancers amongst both healthcare professionals and the general public and develop a patient-centred collaborative approach to cancer treatment and support services. This paper describes the project's development of a range of community outreach events and a training scheme for primary healthcare professionals designed to improve familial cancer referral rates in Leicester. Following consultation with patients and support groups, a series of interactive 'medical supermarket' events were held in Leicester. These events focused on providing patients with a forum for sharing research data, information about diagnosis and treatments and access to support groups and other allied healthcare services with additional information being made available digitally via SFWC webpages and a series of short videos available on a YouTube channel. Qualitative and quantitative data presented here indicate that the SFWC medical supermarket model has been well received by patients and offers a patient-centred, holistic approach to cancer treatment.
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http://dx.doi.org/10.1007/s10689-015-9815-yDOI Listing
December 2015

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

Breast Cancer Res 2015 Apr 25;17:61. Epub 2015 Apr 25.

Holy Cross Hospital, Michael and Dianne Bienes Comprehensive Cancer Center, Fort Lauderdale, FL, USA.

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.

Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.

Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.

Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
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http://dx.doi.org/10.1186/s13058-015-0567-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478717PMC
April 2015

The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services.

Breast Cancer Res 2014 Sep 19;16(5):442. Epub 2014 Sep 19.

Introduction: It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery.

Methods: To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A consortium of over 30 breast cancer family history clinics that have contributed to two research studies on early breast surveillance were asked to participate as well as 10 genetics centres. Monthly referrals to each service were collated and increases from 2012 to 2013 assessed.

Results: Data from 12 family history clinics and 9 regional genetics services showed a rise in referrals from May 2013 onwards. Referrals were nearly 2.5 fold in June and July 2013 from 1,981 (2012) to 4,847 (2013) and remained at around two-fold to October 2013. Demand for BRCA1/2 testing almost doubled and there were also many more enquiries for risk reducing mastectomy. Internal review shows that there was no increase in inappropriate referrals.

Conclusions: The Angelina Jolie effect has been long lasting and global, and appears to have increased referrals to centres appropriately.
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http://dx.doi.org/10.1186/s13058-014-0442-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303122PMC
September 2014

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Cancer Epidemiol Biomarkers Prev 2015 Jan 21;24(1):308-16. Epub 2014 Oct 21.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-0532DOI Listing
January 2015
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