Publications by authors named "Judy Kirk"

92 Publications

Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.

Genet Med 2021 Aug 12. Epub 2021 Aug 12.

The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, NSW, Sydney, Australia.

Purpose: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes.

Methods: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline.

Results: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress.

Conclusion: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.
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http://dx.doi.org/10.1038/s41436-021-01292-wDOI Listing
August 2021

What happens after menopause? (WHAM): A prospective controlled study of vasomotor symptoms and menopause-related quality of life 12 months after premenopausal risk-reducing salpingo-oophorectomy.

Gynecol Oncol 2021 Oct 24;163(1):148-154. Epub 2021 Jul 24.

Centre for Longitudinal and Life Course Research, School of Public Health, University of Queensland, Brisbane, Queensland, Australia.

Objective: To measure menopausal symptoms and quality of life up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) and to measure the effects of hormone therapy.

Methods: Prospective observational study of 95 premenopausal women planning RRSO and a comparison group of 99 who retained their ovaries. Vasomotor symptoms and menopausal-related quality of life (QoL) were measured by the Menopause-Specific QoL Intervention scale at baseline, 3, 6 and 12 months. Chi-square tests measured differences in prevalence of vasomotor symptoms between RRSO vs the comparison group and by hormone therapy use. Change in QoL were examined with multilevel modelling.

Results: Three months after RRSO hot flush prevalence increased from 5.3% to 56.2% and night sweats from 20.2% to 47.2%. Symptoms did not worsen between 3 and 12 months and remained unchanged in the comparison group (p<0.001). After RRSO, 60% commenced hormone therapy. However, 40% of hormone therapy uses continued to experience vasomotor symptoms. After RRSO, 80% of non-hormone therapy users reported vasomotor symptoms. Regardless of hormone therapy use, 86% categorized their vasomotor symptoms as "mild" after RRSO. Following RRSO, Menopause-related QoL deteriorated but was stable in the comparison group (adjusted coefficient = 0.75, 95%CI = 0.55-0.95). After RRSO, QoL was better in hormone therapy users vs non-users (adjusted coefficient = 0.49, 95%CI = 0.20-0.78).

Conclusions: Vasomotor symptoms increase by 3 months after RRSO but do not worsen over the next 12 months. Hormone Therapy reduces but does not resolve vasomotor symptoms and may improve QoL, but not to pre-oophorectomy levels.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.029DOI Listing
October 2021

What happens after menopause? (WHAM): A prospective controlled study of sleep quality up to 12 months after premenopausal risk-reducing salpingo-oophorectomy.

Gynecol Oncol 2021 Aug 8;162(2):447-453. Epub 2021 Jun 8.

Center for Health Sciences, SRI International, California, USA.

Objective: Sleep difficulties impair function and increase the risk of depression at menopause and premenopausal oophorectomy may further worsen sleep. However, prospective data are limited, and it remains uncertain whether Hormone Therapy (HT) improves sleep. This prospective observational study measured sleep quality before and up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) compared to a similar age comparison group who retained their ovaries.

Methods: Ninety-five premenopausal women undergoing RRSO and 99 comparisons were evaluated over a 12-month period using the Pittsburgh Sleep Quality Index (PSQI).

Results: Almost half reported poor sleep quality at baseline. Overall sleep quality was not affected by RRSO until 12 months (p = 0.007). However, sleep disturbance increased by 3 months and remained significantly elevated at 12 months (p < 0.001). Trajectory analysis demonstrated that 41% had increased sleep disturbance after RRSO which persisted in 17.9%. Risk factors for sleep disturbance included severe vasomotor symptoms, obesity and smoking. Around 60% initiated HT after RRSO. Sleep quality was significantly better in HT users vs non users (p = 0.020) but HT did not restore sleep quality to baseline levels.

Conclusions: Overall sleep quality is not affected by RRSO, but new onset sleep disturbance is common, particularly in those with severe vasomotor symptoms. Clinicians should be alert to new-onset sleep disturbance and the potential for HT to improve sleep quality.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.036DOI Listing
August 2021

Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development.

Cancers (Basel) 2021 04 7;13(8). Epub 2021 Apr 7.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.

Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas ( = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set ( = 59,095). Ancestry-matched case-control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted , , , and as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (, , ) or base excision (, ) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases.
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http://dx.doi.org/10.3390/cancers13081762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067736PMC
April 2021

Helping young children understand inherited cancer predisposition syndromes using bibliotherapy.

J Genet Couns 2021 08 31;30(4):1119-1132. Epub 2021 Mar 31.

Hereditary Cancer Clinic, Illawarra Cancer Care Centre, Wollongong, NSW, Australia.

Communication with children about hereditary conditions in the family can be difficult for parents. Yet, good communication strategies are leading determinants of adaptation and resilience. With inherited cancer predisposition syndromes that can affect young children such as Li-Fraumeni syndrome (LFS) and hereditary pheochromocytoma and paraganglioma syndrome (HPPS), genetic testing and subsequent surveillance in at-risk children is the optimal intervention. Given testing often commences early, providing children and their parents with appropriate genetic counseling and communication strategies is important for informed decision making. To inform such communication strategies, we used a bibliotherapeutic framework, where stories are delivered prescriptively (i.e., 'bibliotherapy'), to develop a psycho-educational resource for children aged 5-10 years old at risk of either LFS or HPPS. Illustrated storybooks for children were created based on models of developmental comprehension. To ascertain their experience, parents were invited to read a storybook to their child/ren and participate in semi-structured qualitative interviews. Transcripts were analyzed thematically using a general inductive approach. The bibliotherapeutic resource reportedly supported parents with communication about these issues without raising emotional distress in either themselves or their children. The key stages of a bibliotherapeutic interaction were facilitated by the use of this resource, and all parents reported that it would have been useful when their children were first tested and/or diagnosed. This study lays the foundation for the application of bibliotherapy as a psycho-educational intervention in genetic counseling and demonstrates that bibliotherapy may improve the process of communication between parents and children regarding pediatric-inherited cancer syndromes.
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http://dx.doi.org/10.1002/jgc4.1396DOI Listing
August 2021

A prospective controlled study of sexual function and sexually related personal distress up to 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Menopause 2021 03 15;28(7):748-755. Epub 2021 Mar 15.

Department of Obstetrics and Gynaecology, University of Melbourne and The Royal Women's Hospital, Melbourne, Australia.

Objective: Premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) may impair sexual function, but the nature and degree of impairment and impact of estrogen therapy on sexual function and sexually related personal distress after RRBSO are uncertain.

Methods: Prospective observational study of 73 premenopausal women at elevated risk of ovarian cancer planning RRBSO and 68 premenopausal controls at population risk of ovarian cancer. Participants completed the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. Change from baseline in sexual function following RRBSO was compared with controls at 12 months according to estrogen therapy use.

Results: Baseline sexual function domains did not differ between controls and those who underwent RRBSO and subsequently initiated (56.2%) or did not initiate (43.8%) estrogen therapy. At 12 months, sexual desire and satisfaction were unchanged in the RRBSO group compared with controls. After RRBSO, nonestrogen therapy users demonstrated significant impairment in sexual arousal (β-coefficient (95% confidence interval) -2.53 (-4.86 to -0.19), P < 0.03), lubrication (-3.40 (-5.84 to -0.96), P < 0.006), orgasm (-1.64 (-3.23 to -0.06), P < 0.04), and pain (-2.70 (-4.59 to 0.82), P < 0.005) compared with controls. Although sexually related personal distress may have been more likely after RRBSO, irrespective of estrogen therapy use, there was insufficient data to formally test this effect.

Conclusions: The findings suggest premenopausal RRBSO adversely affects several aspects of sexual function which may be mitigated by the use of estrogen therapy. Further research is needed to understand the effects of RRBSO on sexual function and sexually related personal distress, and the potential for estrogen therapy to mitigate against any adverse effects.
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http://dx.doi.org/10.1097/GME.0000000000001766DOI Listing
March 2021

Academy of Nutrition and Dietetics and National Kidney Foundation: Revised 2020 Standards of Practice and Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Nephrology Nutrition.

J Ren Nutr 2021 03 26;31(2):100-115.e41. Epub 2021 Feb 26.

Nephrology nutrition encompasses therapeutic and preventive nutrition care for individuals through the life cycle and addresses a variety of kidney disorders. Most nephrology nutrition practice focuses on care of individuals with chronic kidney disease, those on dialysis, and recipients of kidney transplants. The Renal Dietitians Dietetic Practice Group, National Kidney Foundation Council on Renal Nutrition, along with the Academy of Nutrition and Dietetics Quality Management Committee, have revised the Standards of Practice (SOP) and Standards of Professional Performance (SOPP) for RDNs working in nephrology nutrition. The SOP and SOPP for RDNs in Nephrology Nutrition provide indicators that describe three levels of practice: competent, proficient, and expert. The SOP uses the Nutrition Care Process and clinical workflow elements for delivering patient/client care. The SOPP describes the following six domains that focus on professional performance: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Specific indicators outlined in the SOP and SOPP depict how these standards apply to practice. The SOP and SOPP are complementary resources for RDNs and are intended to be used as a self-evaluation tool for assuring competent practice in nephrology nutrition and for determining potential education and training needs for advancement to a higher practice level in a variety of settings.
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http://dx.doi.org/10.1053/j.jrn.2020.12.001DOI Listing
March 2021

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

J Clin Endocrinol Metab 2021 03;106(4):1163-1182

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, Australia.

Context: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.

Objective: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.

Methods: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.

Results: Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.

Conclusion: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
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http://dx.doi.org/10.1210/clinem/dgaa957DOI Listing
March 2021

Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility.

J Med Genet 2020 Nov 9. Epub 2020 Nov 9.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

Background: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles.

Methods: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols.

Results: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information.

Conclusion: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.
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http://dx.doi.org/10.1136/jmedgenet-2020-107140DOI Listing
November 2020

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer.

Nat Med 2020 11 5;26(11):1742-1753. Epub 2020 Oct 5.

Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
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http://dx.doi.org/10.1038/s41591-020-1072-4DOI Listing
November 2020

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

JAMA Oncol 2020 08;6(8):1218-1230

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, And Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes And Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions And Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
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http://dx.doi.org/10.1001/jamaoncol.2020.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333177PMC
August 2020

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Nat Genet 2020 01 7;52(1):56-73. Epub 2020 Jan 7.

Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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http://dx.doi.org/10.1038/s41588-019-0537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974400PMC
January 2020

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

BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry.

Hum Mutat 2019 10 3;40(10):1781-1796. Epub 2019 Jul 3.

Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.
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http://dx.doi.org/10.1002/humu.23804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764847PMC
October 2019

GP attitudes to and expectations for providing personal genomic risk information to the public: a qualitative study.

BJGP Open 2019 Apr 20;3(1):bjgpopen18X101633. Epub 2019 Feb 20.

Associate Professor, Cancer Epidemiology and Prevention Research, Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Background: As part of a pilot randomised controlled trial examining the impact of personal melanoma genomic risk information on behavioural and psychosocial outcomes, GPs were sent a booklet containing their patient's genomic risk of melanoma.

Aim: Using this booklet as an example of genomic risk information that might be offered on a population-level in the future, this study explored GP attitudes towards communicating genomic risk information and resources needed to support this process.

Design & Setting: Semi-structured interviews were conducted with 22 Australian GPs.

Method: The interviews were recorded and transcribed, and data were analysed thematically.

Results: GPs in this sample believed that communicating genomic risk may become a responsibility within primary care and they recommended a shared decisionmaking approach to guide the testing process. Factors were identified that may influence how and when GPs communicate genomic risk information. GPs view genomics-based risk as one of many disease risk factors and feel that this type of information could be applied in practice in the context of overall risk assessment for diseases for which prevention and early detection strategies are available. They believe it is important to ensure that patients understand their genomic risk and do not experience long-term adverse psychological responses. GPs desire clinical practice guidelines that specify recommendations for genomic risk assessment and patient management, point-of-care resources, and risk prediction tools that include genomic and traditional risk factors.

Conclusion: These findings will inform the development of resources for preparing GPs to manage and implement genomic risk information in practice.
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http://dx.doi.org/10.3399/bjgpopen18X101633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480852PMC
April 2019

Assessing the medical workforces perceived barriers to the prescription of risk-reducing medication for women at high-risk of breast cancer.

Breast J 2019 01 7;25(1):34-40. Epub 2018 Dec 7.

Department of Medical Oncology, Concord Repatriation General Hospital, Concord, NSW, Australia.

This study aims to determine the attitudes and barriers of Australian oncology health professionals towards using tamoxifen as a breast cancer risk-reducing medication (RRM). Our target group was health professionals involved in breast cancer risk assessment or treatment. Members of relevant medical organizations in Australia and New Zealand were invited to participate in a web-based survey assessing: their attitudes towards tamoxifen as a RRM; which health professionals they felt were responsible for initiating and monitoring women on RRM and their views on workforce issues related to RRM prescription. There were 100 respondents, including 33 genetic health professionals, 32 medical oncologists and 20 surgeons. Respondents perceived tamoxifen to be effective as a RRM (99%). However, only 41% of prescribing health professionals (n = 64) had ever prescribed tamoxifen as a RRM. Overall, survey respondents felt that the initiation of RRM was the role of specialists. Assessing a patient's risk of breast cancer was reported to be the role of cancer geneticists/familial cancer clinicians (74%) and medical oncologists (66%). Discussion about the use of RRM was reported to be the role of these same groups (84% and 85% respectively). Medical oncologists (83%) and breast physicians (70%) were most frequently considered to be responsible for initiating the prescription and monitoring women once commenced on RRM (72% and 71% respectively). Oncology health professionals express confidence in the effectiveness of tamoxifen as a RRM despite reporting low prescription rates. Findings demonstrate that these oncology health professionals felt that initiation of RRM was the role of cancer specialists, despite preventative medicine being seen as a primary care activity. If uptake among at-risk women increases, this will put a significant burden on cancer services and GPs will need to take on a greater role in the delivery of RRM.
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http://dx.doi.org/10.1111/tbj.13157DOI Listing
January 2019

Medicare-funded cancer genetic tests: a note of caution.

Med J Aust 2018 08;209(5):193-196

Prince of Wales Hospital and Community Health Services, Sydney, NSW.

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http://dx.doi.org/10.5694/mja17.01124DOI Listing
August 2018

The melanoma genomics managing your risk study: A protocol for a randomized controlled trial evaluating the impact of personal genomic risk information on skin cancer prevention behaviors.

Contemp Clin Trials 2018 07 23;70:106-116. Epub 2018 May 23.

Cancer Epidemiology and Prevention Research, Sydney School of Public Health, The University of Sydney, NSW 2006, Australia; Melanoma Institute Australia, The University of Sydney, NSW 2006, Australia.

Background: Reducing ultraviolet radiation (UV) exposure and improving early detection may reduce melanoma incidence, mortality and health system costs. This study aims to evaluate the efficacy and cost-effectiveness of providing information on personal genomic risk of melanoma in reducing UV exposure at 12 months, according to low and high traditional risk.

Methods: In this randomized controlled trial, participants (target sample = 892) will be recruited from the general population, and randomized (1:1 ratio, intervention versus control). Intervention arm participants provide a saliva sample, receive personalized melanoma genomic risk information, a genetic counselor phone call, and an educational booklet on melanoma prevention. Control arm participants receive only the educational booklet. Eligible participants are aged 18-69 years, have European ancestry and no personal history of melanoma. All participants will complete a questionnaire and wear a UV dosimeter to objectively measure their sun exposure at baseline, 1- and 12-month time-points, except 1-month UV dosimetry will be limited to ~250 participants. The primary outcome is total daily Standard Erythemal Doses at 12 months. Secondary outcomes include objectively measured UV exposure for specific time periods (e.g. midday hours), self-reported sun protection and skin-examination behaviors, psycho-social outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the intervention costs and outcomes.

Discussion: This trial will inform the clinical and personal utility of introducing genomic testing into the health system for melanoma prevention and early detection at a population-level.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12617000691347.
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http://dx.doi.org/10.1016/j.cct.2018.05.014DOI Listing
July 2018

Distress, uncertainty, and positive experiences associated with receiving information on personal genomic risk of melanoma.

Eur J Hum Genet 2018 08 30;26(8):1094-1100. Epub 2018 Apr 30.

Cancer Epidemiology and Prevention Research, Sydney School of Public Health, The University of Sydney, Sydney, Australia.

The aim of this research was to understand how genomics-based personal melanoma risk information impacts psychological and emotional health outcomes in the general population. In a pilot randomized controlled trial, participants (n = 103) completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire, 3 months after receiving personal melanoma genomic risk information. Mean scores for MICRA items and subscales were stratified by genomic risk group (low, average, high), gender, education, age, and family history of melanoma. P values were obtained from t-tests and analysis of variance tests. We found that overall, participants (mean age: 53 years, range: 21-69; 52% female) had a total MICRA mean score of 18.6 (standard deviation: 11.1, range: 1-70; possible range: 0-105). The high genomic risk group had higher mean scores for the total (24.2, F = 6.7, P = 0.0019), distress (3.3, F = 9.4, P = 0.0002) and uncertainty (8.5, F = 6.5, P = 0.0021) subscales compared with average (17.6, 1.1, and 4.5, respectively) and low-risk groups (14.1, 0.5, and 2.5, respectively). Positive experiences scores were consistent across risk groups. In conclusion, MICRA scores for the total, distress and uncertainty subscales in our study were relatively low overall, but people who receive a high genomic risk result may benefit from increased support following testing.
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http://dx.doi.org/10.1038/s41431-018-0145-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057946PMC
August 2018

Psychological outcomes and surgical decisions after genetic testing in women newly diagnosed with breast cancer with and without a family history.

Eur J Hum Genet 2018 07 30;26(7):972-983. Epub 2018 Mar 30.

Familial Cancer Service, Westmead Hospital, Hawkesbury Road, Westmead, NSW, 2145, Australia.

In patients with early breast cancer, personal and tumour characteristics other than family history are increasingly used to prompt genetic testing to guide women's cancer management (treatment-focused genetic testing, 'TFGT'). Women without a known strong family history of breast and/or ovarian may be more vulnerable to psychological sequelae arising from TFGT. We compared the impact of TFGT in women with (FH+) and without (FH-) a strong family history on psychological adjustment and surgical decisions. Women aged <50 years with high-risk features were offered TFGT before definitive breast cancer surgery and completed self-report questionnaires at four time points over 12 months. All 128 women opted for TFGT. TFGT identified 18 carriers of a disease-causing variant (50.0% FH+) and 110 non-carriers (59.1% FH+). There were no differences based on family history in bilateral mastectomy (BM) uptake, p = .190, or uptake of risk-reducing bilateral salpingo-oophorectomy (RRBSO), p = .093. FH- women had lower decreases in anxiety a year after diagnosis, p = .011, and regret regarding their decision whether to undergo BM, p = .022, or RRBSO, p = .016 than FH + women. FH- carriers reported significantly higher regret regarding their TFGT choice (p = .024) and test-related distress (p = .012) than FH + carriers, but this regret/distress could not be attributed to a concern regarding a possible worse prognosis. These findings indicate that FH- women may require additional counselling to facilitate informed decisions. Carriers without a family history may require additional follow-up counselling to facilitate psychological adjustment to their positive variant results, extra support in making surgical decisions, and counselling about how best to communicate results to family members.
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http://dx.doi.org/10.1038/s41431-017-0057-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018744PMC
July 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

Development and Evaluation of a Telephone Communication Protocol for the Delivery of Personalized Melanoma Genomic Risk to the General Population.

J Genet Couns 2018 04 3;27(2):370-380. Epub 2017 Dec 3.

Cancer Epidemiology and Prevention Research, Sydney School of Public Health, The University of Sydney, Level 6 - North, The Lifehouse, 119-143 Missenden Rd, Camperdown, NSW, 2050, Australia.

Communicating personalized genomic risk results for common diseases to the general population as a form of tailored prevention is novel and may require alternative genetic counseling service delivery models. We describe the development and evaluation of a communication protocol for disclosing melanoma genomic risk information to the asymptomatic general population and assess participants' satisfaction and acceptability. Participants (n = 117) were aged 22-69 years, living in New South Wales, Australia and unselected for family history. They provided a saliva sample and had genomic testing for melanoma for low to moderate penetrant melanoma susceptibility variants in 21 genes. Participants could choose to receive their results from a genetic counselor via telephone, followed by a mailed booklet or to receive their risk result via mailed booklet only with a follow-up call for those at high risk. A follow-up questionnaire was completed by 85% of participants 3-months later. Most participants (80%) elected to receive their result via telephone. Participants were highly satisfied with the delivery of results (mean 3.4 out of 4, standard deviation 0.5), and this did not differ by delivery mode, risk category, age or sex. On follow-up, 75% accurately recalled their risk category, 6% indicated a preference for a different delivery mode, either electronic or face-to-face. The process of disclosing genomic risk results to the general population over the telephone with accompanying written material was feasible and acceptable, and may be useful for communicating polygenic risk for common diseases in the context of increasing demands for genomic testing.
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http://dx.doi.org/10.1007/s10897-017-0183-7DOI Listing
April 2018

Facilitating decision-making in women undergoing genetic testing for hereditary breast cancer: BRECONDA randomized controlled trial results.

Breast 2017 Dec 12;36:79-85. Epub 2017 Oct 12.

Westmead Breast Cancer Institute, Westmead Hospital, Sydney, Australia.

Background: Decision-making concerning risk-reducing mastectomy for women at hereditary risk of breast cancer entails complex personal choices. Deciding whether and how to restore breast shape after risk-reducing mastectomy is a key part of this process. We developed a web-based decision aid, BRECONDA (Breast Reconstruction Decision Aid), to assist women in decision-making regarding breast reconstruction.

Method: This study assessed the efficacy of BRECONDA to assist women at increased risk of breast cancer in making decisions regarding risk-reducing mastectomy in terms of decisional conflict, knowledge, and satisfaction with information. Women at hereditary risk of breast cancer (N = 64) were recruited into this randomized controlled trial from four Australian hereditary cancer clinics. Participants initially provided online consent and completed baseline questionnaires assessing decisional conflict, knowledge, and satisfaction with information. They were then randomly assigned to either: 1) Intervention - unlimited access to BRECONDA, with usual care; or, 2) Control - usual care. At 2-months follow-up (N = 60) the outcomes were re-assessed. Intervention participants also completed user acceptability ratings for the intervention overall and specific key modules.

Results: MANCOVA analyses indicated that Intervention participants reported lower decisional conflict (P = 0.027), and greater knowledge (P = 0.019) and satisfaction with information (P < 0.0005) at 2-months follow-up compared with Controls. Intervention participants reported high user acceptability and satisfaction with the intervention.

Conclusion: BRECONDA benefits women considering risk-reducing mastectomy by reducing decisional conflict, and improving knowledge and satisfaction with information. These benefits, coupled with high user acceptability, demonstrate the feasibility of implementing BRECONDA in the hereditary cancer risk context.
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http://dx.doi.org/10.1016/j.breast.2017.10.001DOI Listing
December 2017

Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

Gynecol Oncol 2017 11 17;147(2):381-387. Epub 2017 Aug 17.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Electronic address:

Objective: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives.

Methods: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression.

Results: Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (P=4.43×10), and with increasing numbers of Lynch cancers in relatives (P≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004).

Conclusion: The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.
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http://dx.doi.org/10.1016/j.ygyno.2017.08.011DOI Listing
November 2017

Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing.

Mod Pathol 2017 08 28;30(8):1048-1068. Epub 2017 Apr 28.

Familial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney Medical School, University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Endometrial cancer is the most common gynecological cancer, but is nevertheless uncommon enough to have value as a signature cancer for some hereditary cancer syndromes. Commercial multigene testing panels include up to 13 different genes annotated for germline DNA testing of patients with endometrial cancer. Many other genes have been reported as relevant to familial endometrial cancer from directed genome-wide sequencing studies or multigene panel testing, or research. This review assesses the evidence supporting association with endometrial cancer risk for 32 genes implicated in hereditary endometrial cancer, and presents a summary of rare germline variants in these 32 genes detected by analysis of quasi-population-based endometrial cancer patients from The Cancer Genome Atlas project. This comprehensive investigation has led to the conclusion that convincing evidence currently exists to support clinical testing of only six of these genes for diagnosis of hereditary endometrial cancer. Testing of endometrial cancer patients for the remaining genes should be considered in the context of research studies, as a means to better establish the level of endometrial cancer risk, if any, associated with genetic variants that are deleterious to gene or protein function. It is acknowledged that clinical testing of endometrial cancer patients for several genes included on commercial panels may provide actionable findings in relation to risk of other cancers, but these should be considered secondary or incidental findings and not conclusive evidence for diagnosis of inherited endometrial cancer. In summary, this review and analysis provides a comprehensive report of current evidence to guide the selection of genes for clinical and research gene testing of germline DNA from endometrial cancer patients.
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http://dx.doi.org/10.1038/modpathol.2017.20DOI Listing
August 2017

Psychosocial morbidity in TP53 mutation carriers: is whole-body cancer screening beneficial?

Fam Cancer 2017 07;16(3):423-432

Familial Cancer Clinic, Peter MacCallum Cancer Centre, E. Melbourne, VIC, 3002, Australia.

Germline TP53 mutation carriers are at high risk of developing a range of cancers. Effective cancer risk management is an important issue for these individuals. We assessed the psychosocial impact in TP53 mutation carriers of WB-MRI screening as part of the Surveillance in Multi-Organ Cancer (SMOC+) protocol, measuring their unmet needs, anxiety and depression levels as well as cancer worry using psychological questionnaires and in-depth interviews about their experiences of screening. We present preliminary psychosocial findings from 17 participants during their first 12 months on the trial. We found a significant reduction in participants' mean anxiety from baseline to two weeks post WB-MRI (1.2, 95% CI 0.17 to 2.23 p = 0.025), indicative of some benefit. Emerging qualitative themes show most participants are emotionally supported and contained by the screening program and are motivated by their immediate concern about staying alive, despite being informed about the current lack of evidence around efficacy of screening for people with TP53 mutations in terms of cancer morbidity or mortality. For those that do gain emotional reassurance from participating in the screening study, feelings of abandonment by the research team are a risk when the study ends. For others, screening was seen as a burden, consistent with the relentless nature of cancer risk associated with Li-Fraumeni syndrome, though these patients still declared they wished to participate due to their concern with staying alive. Families with TP53 mutations need ongoing support due to the impact on the whole family system. These findings suggest a comprehensive multi-organ screening program for people with TP53 mutations provides psychological benefit independent of an impact on cancer morbidity and mortality associated with the syndrome. The benefits of a multi-organ screening program will be greater still if the screening tests additionally reduce the cancer morbidity and mortality associated with the syndrome. These findings may also inform the care of individuals and families with other multi-organ cancer predisposition syndromes.
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http://dx.doi.org/10.1007/s10689-016-9964-7DOI Listing
July 2017

Happy New Year!

Authors:
Judy Kirk

J Ren Nutr 2017 01;27(1):72-73

Rochester Regional Health System, Rochester, New York. Electronic address:

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http://dx.doi.org/10.1053/j.jrn.2016.10.004DOI Listing
January 2017

Qualitatively understanding patients' and health professionals' experiences of the BRECONDA breast reconstruction decision aid.

Psychooncology 2017 Oct 30;26(10):1618-1624. Epub 2017 Jan 30.

Hereditary Cancer Clinic, Prince of Wales Hospital, Sydney, Australia.

Objective: Women diagnosed with breast cancer or ductal carcinoma in situ and those with a genetic susceptibility to developing this disease face the challenging decision of whether or not to undergo breast reconstruction following mastectomy. As part of a large randomized controlled trial, this qualitative study examined women's experiences of using the Breast RECONstruction Decision Aid (BRECONDA) and health professionals' feedback regarding the impact of this resource on patients' knowledge and decision making about breast reconstruction.

Method: Semistructured interviews were conducted with women who accessed the BRECONDA intervention (N = 36) and with their healthcare providers (N = 6). All interviews were transcribed verbatim and subjected to thematic analysis by 3 independent coders.

Results: Participants reported an overall positive impression, with all interviewees endorsing this decision aid as a useful resource for women considering reconstructive surgery. Thematic analysis of patient interviews revealed 4 themes: overall impressions and aesthetics; personal relevance and utility; introducing BRECONDA; and advantages and suggested improvements. Analysis of health professionals' interviews also revealed 4 themes: need for BRECONDA, impact of BRECONDA, potential difficulties that may arise in using the decision aid, and recommending BRECONDA to patients. Patients indicated that they derived benefit from this resource at all stages of their decision-making process, with the greatest perceived benefit being for those early in their breast reconstruction journey.

Conclusion: These findings support the use of BRECONDA as an adjunct to clinical consultation and other information sources.
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http://dx.doi.org/10.1002/pon.4346DOI Listing
October 2017

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

Breast Cancer Res Treat 2017 01 28;161(1):117-134. Epub 2016 Oct 28.

Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.

Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.

Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.

Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.

Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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http://dx.doi.org/10.1007/s10549-016-4018-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222911PMC
January 2017
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