Publications by authors named "Ian G Campbell"

183 Publications

Evaluation of two population screening programmes for founder mutations in the Australian Jewish community: a protocol paper.

BMJ Open 2021 06 25;11(6):e041186. Epub 2021 Jun 25.

Hereditary Cancer Centre, Prince of Wales Hospital Cancer Services, Randwick, New South Wales, Australia.

Introduction: People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific pathogenic variants, referred to as -Jewish founder mutations (B-JFM), account for >90% of pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study-a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia.

Methods And Analysis: To rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared.

Ethics And Dissemination: Institutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125.Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-041186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237737PMC
June 2021

Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study.

NPJ Breast Cancer 2021 Jun 11;7(1):76. Epub 2021 Jun 11.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon-intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10) and missense (OR 1.27, p = 3.96 × 10) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2-4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-021-00279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196173PMC
June 2021

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

NPJ Breast Cancer 2021 May 12;7(1):52. Epub 2021 May 12.

School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-021-00255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115524PMC
May 2021

Longitudinal Analysis of Sleep Spindle Maturation from Childhood through Late Adolescence.

J Neurosci 2021 May 30;41(19):4253-4261. Epub 2021 Mar 30.

Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, California 95817.

Sleep spindles are intermittent bursts of 11-15 Hz EEG waves that occur during non-rapid eye movement sleep. Spindles are believed to help maintain sleep and to play a role in sleep-dependent memory consolidation. Here we applied an automated sleep spindle detection program to our large longitudinal sleep EEG dataset (98 human subjects, 6-18 years old, >2000 uninterrupted nights) to evaluate maturational trends in spindle wave frequency, density, amplitude, and duration. This large dataset enabled us to apply nonlinear as well as linear age models, thereby extending the findings of prior cross-sectional studies that used linear models. We found that spindle wave frequency increased with remarkable linearity across the age range. Central spindle density increased nonlinearly to a peak at age 15.1 years. Central spindle wave amplitude declined in a sigmoidal pattern with the age of fastest decline at 13.5 years. Spindle duration decreased linearly with age. Of the four measures, only spindle amplitude showed a sex difference in dynamics such that the age of most rapid decline in females preceded that in males by 1.4 years. This amplitude pattern, including the sex difference in timing, paralleled the maturational pattern for δ (1-4 Hz) wave power. We interpret these age-related changes in spindle characteristics as indicators of maturation of thalamocortical circuits and changes in sleep depth. These robust age-effects could facilitate the search for cognitive-behavioral correlates of spindle waveforms and might also help guide basic research on EEG mechanisms and postnatal brain maturation. The brain reorganization of adolescence produces massive changes in sleep EEG. These changes include the morphology and abundance of sleep spindles, an EEG marker of non-rapid eye movement sleep believed to reflect offline memory processes and/or protection of the sleep state. We analyzed >2000 nights of longitudinal sleep EEG from 98 subjects (age 6-18 years old) to investigate maturational changes in spindle amplitude, frequency, density, and duration. The large dataset enabled us to detect nonlinear as well as linear age changes. All measures showed robust age effects that we hypothesize reflect the maturation of thalamocortical circuits and decreasing sleep depth. These findings could guide further research into the cognitive-behavioral correlates of sleep spindles and their underlying brain mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2370-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143202PMC
May 2021

Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study.

Cancer Chemother Pharmacol 2021 Jul 23;88(1):39-52. Epub 2021 Mar 23.

Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Purpose: Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response).

Methods: Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-Tc-IDA, data derived for hepatic extraction/excretion parameters (CL, T, 1hRET, HEF, T). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS).

Results: N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CL, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CL, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T, XDH (rs 207440), and ABCB11 (rs 4148777).

Conclusions: Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients.

Australian New Zealand Clinical Trials Registry (anzctr) Number: ACTRN12610000897066, Date registered: 21/10/2010.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-021-04264-8DOI Listing
July 2021

Effects of sleep restriction on the sleep electroencephalogram of adolescents.

Sleep 2021 06;44(6)

Department of Psychiatry, University of California Davis.

Study Objectives: This report describes findings from an ongoing longitudinal study of the effects of varied sleep durations on wake and sleep electroencephalogram (EEG) and daytime function in adolescents. Here, we focus on the effects of age and time in bed (TIB) on total sleep time (TST) and nonrapid eye movement (NREM) and rapid eye movement (REM) EEG.

Methods: We studied 77 participants (41 male) ranging in age from 9.9 to 16.2 years over the 3 years of this study. Each year, participants adhered to each of three different sleep schedules: four consecutive nights of 7, 8.5, or 10 h TIB.

Results: Altering TIB successfully modified TST, which averaged 406, 472 and 530 min on the fourth night of 7, 8.5, and 10 h TIB, respectively. As predicted by homeostatic models, shorter sleep durations produced higher delta power in both NREM and REM although these effects were small. Restricted sleep more substantially reduced alpha power in both NREM and REM sleep. In NREM but not REM sleep, sleep restriction strongly reduced both the all-night accumulation of sigma EEG activity (11-15 Hz energy) and the rate of sigma production (11-15 Hz power).

Conclusions: The EEG changes in response to TIB reduction are evidence of insufficient sleep recovery. The decrease in sigma activity presumably reflects depressed sleep spindle activity and suggests a manner by which sleep restriction reduces waking cognitive function in adolescents. Our results thus far demonstrate that relatively modest TIB manipulations provide a useful tool for investigating adolescent sleep biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsaa280DOI Listing
June 2021

Primary mucinous ovarian neoplasms rarely show germ cell histogenesis.

Histopathology 2021 03 29;78(4):640-642. Epub 2020 Dec 29.

Peter MacCallum Cancer Centre, Melbourne, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14297DOI Listing
March 2021

Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities.

J Pathol 2021 01 28;253(1):41-54. Epub 2020 Oct 28.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5545DOI Listing
January 2021

The TP53 mutation rate differs in breast cancers that arise in women with high or low mammographic density.

NPJ Breast Cancer 2020 7;6:34. Epub 2020 Aug 7.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC Australia.

Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available ( = 842) were identified from the Lifepool cohort of >54,000 women participating in population-based mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available ( = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low- and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-020-00176-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414106PMC
August 2020

Molecular comparison of pure ovarian fibroma with serous benign ovarian tumours.

BMC Res Notes 2020 Jul 22;13(1):349. Epub 2020 Jul 22.

Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Australia.

Objective: Ovarian fibromas and adenofibromas are rare ovarian tumours. They are benign tumours composed of spindle-like stromal cells (pure fibroma) or a mixture of fibroblast and epithelial components (adenofibroma). We have previously shown that 40% of benign serous ovarian tumours are likely primary fibromas due to the neoplastic alterations being restricted to the stromal compartment of these tumours. We further explore this finding by comparing benign serous tumours to pure fibromas.

Results: Performing copy number aberration (CNA) analysis on the stromal component of 45 benign serous tumours and 8 pure fibromas, we have again shown that trisomy of chromosome 12 is the most common aberration in ovarian fibromas. CNAs were more frequent in the pure fibromas than the benign serous tumours (88% vs 33%), however pure fibromas more frequently harboured more than one CNA event compared with benign serous tumours. As these extra CNA events observed in the pure fibromas were unique to this subset our data indicates a unique tumour evolution. Gene expression analysis on the two cohorts was unable to show gene expression changes that differed based on tumour subtype. Exome analysis did not reveal any recurrently mutated genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13104-020-05194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376903PMC
July 2020

Population-based targeted sequencing of 54 candidate genes identifies as a susceptibility gene for high-grade serous ovarian cancer.

J Med Genet 2021 May 16;58(5):305-313. Epub 2020 Jun 16.

Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Catalunya, Spain.

Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.

Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.

Results: The ORs associated for high-grade serous ovarian cancer were 3.01 for (95% CI 1.59 to 5.68; p=0.00068), 1.99 for (95% CI 1.15 to 3.43; p=0.014) and 4.07 for (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for in high-grade serous ovarian cancer is likely to represent a true positive.

Conclusions: We have found strong evidence that carriers of deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086250PMC
May 2021

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

BMC Cancer 2020 May 1;20(1):369. Epub 2020 May 1.

Research Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre Building, 305 Grattan St., Melbourne, Victoria, VIC 3000, Australia.

Background: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours.

Methods: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH.

Results: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified.

Conclusion: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-6705-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195761PMC
May 2020

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes.

Nat Commun 2020 04 2;11(1):1640. Epub 2020 Apr 2.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15461-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118163PMC
April 2020

The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma.

NPJ Breast Cancer 2020 12;6. Epub 2020 Mar 12.

1Peter MacCallum Cancer Centre, Melbourne, VIC Australia.

Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP, mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-020-0150-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067788PMC
March 2020

Therapeutic options for mucinous ovarian carcinoma.

Gynecol Oncol 2020 03 2;156(3):552-560. Epub 2020 Jan 2.

Peter MacCallum Cancer Centre, Melbourne, Australia.

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents.

Methods: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166).

Results: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184).

Conclusions: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056511PMC
March 2020

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Cancer Res 2020 02 13;80(3):624-638. Epub 2019 Nov 13.

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; = 0.0002). No genotype-phenotype associations were detected for PSVs in . These results demonstrate that specific PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553241PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

The molecular origin and taxonomy of mucinous ovarian carcinoma.

Nat Commun 2019 09 2;10(1):3935. Epub 2019 Sep 2.

Peter MacCallum Cancer Centre, Melbourne, Australia.

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718426PMC
September 2019

"A Natural Progression": Australian Women's Attitudes About an Individualized Breast Screening Model.

Cancer Prev Res (Phila) 2019 06 19;12(6):383-390. Epub 2019 Apr 19.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.

Individualized screening is our logical next step to improve population breast cancer screening in Australia. To explore breast screening participants' views of the current program in Victoria, Australia, examine their openness to change, and attitudes toward an individualized screening model, this qualitative work was performed from a population-based breast screening cohort. This work was designed to inform the development of a decision aid to facilitate women's decisions about participating in individualized screening, and to elicit Australian consumer perspectives on the international movement toward individualized breast screening. A total of 52 women participated in one of four focus groups, and were experienced with screening with 90% of participants having had more than three mammograms. Focus group discussion was facilitated following three main themes: (i) experience of breast screening; (ii) breast cancer risk perception, and (iii) views on individualized screening. Participants had strong, positive, emotional ties to breast screening in its current structure but were supportive, with some reservations, of the idea of individualized screening. There was good understanding about the factors contributing to personalized risk and a wide range of opinions about the inclusion of genetic testing with genetic testing being considered a foreign and evolving domain. Individualized breast screening that takes account of risk factors such as mammographic density, lifestyle, and genetic factors would be acceptable to a population of women who are invested in the current system. The communication and implementation of a new program would be critical to its acceptance and potential success. Reservations may be had in regards to uptake of genetic testing, motivations behind the change, and management of the women allocated to a lower risk category.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1940-6207.CAPR-18-0443DOI Listing
June 2019

Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer.

J Natl Cancer Inst 2019 12;111(12):1332-1338

Background: Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast cancer.

Methods: RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analyzed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify biallelic inactivation of RAD51C, copy number variation, mutational signatures, and the spectrum of somatic mutations in breast cancer driver genes. The promoter of RAD51C was analyzed for DNA methylation.

Results: A statistically significant excess of loss-of-function variants was identified in 3080 cases (0.4%) compared with 2 among 4840 controls (0.04%; odds ratio = 8.67, 95% confidence interval = 1.89 to 80.52, P< .001), with more than half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with estrogen-negative (P <. 001) or triple-negative cancer (P < .001), but not in estrogen-positive cases. Tumor sequencing from carriers confirmed bi-allelic inactivation in all the triple-negative cases and was associated with high homologous recombination deficiency scores and mutational signature 3 indicating homologous recombination repair deficiency.

Conclusions: This study provides evidence that germline loss-of-function variants of RAD51C are associated with hereditary breast cancer, particularly triple-negative type. RAD51C-null breast cancers possess similar genomic and clinical features to BRCA1-null cancers and may also be vulnerable to DNA double-strand break inducing chemotherapies and poly ADP-ribose polymerase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910168PMC
December 2019

Mechanical-ventilatory responses to peak and ventilation-matched upper- versus lower-body exercise in normal subjects.

Exp Physiol 2019 06 15;104(6):920-931. Epub 2019 Apr 15.

Centre for Human Performance, Exercise and Rehabilitation, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.

New Findings: What is the central question of this study? To what extent are the mechanical-ventilatory responses to upper-body exercise influenced by task-specific locomotor mechanics? What is the main finding and its importance? When compared with lower-body exercise performed at similar ventilations, upper-body exercise was characterized by tidal volume constraint, dynamic lung hyperinflation and an increased propensity towards neuromechanical uncoupling of the respiratory system. Importantly, these responses were independent of respiratory dysfunction and flow limitation. Thus, the mechanical ventilatory responses to upper-body exercise are attributable, in part, to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax).

Abstract: The aim of this study was to determine the extent to which the mechanical ventilatory responses to upper-body exercise are influenced by task-specific locomotor mechanics. Eight healthy men (mean ± SD: age, 24 ± 5 years; mass, 74 ± 11 kg; and stature, 1.79 ± 0.07 m) completed two maximal exercise tests, on separate days, comprising 4 min stepwise increments of 15 W during upper-body exercise (arm-cranking) or 30 W during lower-body exercise (leg-cycling). The tests were repeated at work rates calculated to elicit 20, 40, 60, 80 and 100% of the peak ventilation achieved during arm-cranking ( ). Exercise measures included pulmonary ventilation and gas exchange, oesophageal pressure-derived indices of respiratory mechanics, operating lung volumes and expiratory flow limitation. Subjects exhibited normal resting pulmonary function. Arm-crank exercise elicited significantly lower peak values for work rate, O uptake, CO output, minute ventilation and tidal volume (p < 0.05). At matched ventilations, arm-crank exercise restricted tidal volume expansion relative to leg-cycling exercise at 60% (1.74 ± 0.61 versus 2.27 ± 0.68 l, p < 0.001), 80% (2.07 ± 0.70 versus 2.52 ± 0.67 l, p < 0.001) and 100% (1.97 ± 0.85 versus 2.55 ± 0.72 l, p = 0.002). Despite minimal evidence of expiratory flow limitation, expiratory reserve volume was significantly higher during arm-cranking versus leg-cycling exercise at 100% (39 ± 8 versus 29 ± 8% of vital capacity, p = 0.002). At any given ventilation, arm-cranking elicited greater inspiratory effort (oesophageal pressure) relative to thoracic displacement (tidal volume). Arm-cranking exercise is sufficient to provoke respiratory mechanical derangements (restricted tidal volume expansion, dynamic hyperinflation and neuromechanical uncoupling) in subjects with normal pulmonary function and expiratory flow reserve. These responses are likely to be attributable to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/EP087648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594000PMC
June 2019

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma.

J Pathol 2019 07 22;248(3):326-338. Epub 2019 Apr 22.

Peter MacCallum Cancer Centre, Melbourne, Australia.

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5262DOI Listing
July 2019

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.

Cancer Cell 2019 02;35(2):256-266.e5

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2018.12.011DOI Listing
February 2019

Molecular comparison of interval and screen-detected breast cancers.

J Pathol 2019 06 8;248(2):243-252. Epub 2019 Mar 8.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5251DOI Listing
June 2019

Shorter sleep durations in adolescents reduce power density in a wide range of waking electroencephalogram frequencies.

PLoS One 2019 22;14(1):e0210649. Epub 2019 Jan 22.

University of California, Davis, Department of Psychiatry and Behavioral Sciences, Davis, California, United States of America.

Despite sleep's recognized biological importance, it has been remarkably difficult to demonstrate changes in brain physiology with reduced sleep durations. In a study of adolescents, we varied sleep durations by restricting time in bed for four nights of either 10, 8.5 or 7 h. Shorter sleep durations significantly decreased waking electroencephalogram (EEG) power in a wide range of frequencies with both eyes closed and eyes open in central and occipital leads. These findings suggest new research directions and raise the possibility that waking EEG power density could provide a non-invasive test for biologically sufficient sleep.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342317PMC
October 2019

When Is "Type I" Ovarian Cancer Not "Type I"? Indications of an Out-Dated Dichotomy.

Front Oncol 2018 21;8:654. Epub 2018 Dec 21.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

The dualistic classification of epithelial ovarian cancer (EOC) into "type I" and "type II" is widely applied in the research setting; it is used as a convenient way of conceptualizing different mechanisms of tumorigenesis. However, this classification conflicts with recent molecular insights of the etiology of EOC. Molecular and cell of origin studies indicate that while type II tumors could be classed together, type I tumors are not homogenous, even within the histological types, and can have poor clinical outcomes. Type II high grade serous carcinoma and type I low grade serous carcinomas best fit the description of the dualistic model, with different precursors, and distinct molecular profiles. However, endometriosis-associated cancers should be considered a separate group, without assuming an indolent course or type I genetic profiles. Furthermore, the very clear differences between mucinous ovarian carcinomas and other type I tumors, including an uncertain origin, and heterogeneous mutational spectrum and clinical behavior, indicate a non-type I classification for this entity. The impression that only type II carcinomas are aggressive, have poor prognosis, and carry mutations is an unhelpful misinterpretation of the dualistic classification. In this review, we revisit the history of EOC classification, and discuss the misunderstanding of the dualistic model by comparing the clinical and molecular heterogeneity of EOC types. We also emphasize that all EOC research, both basic and clinical, should consider the subtypes as different diseases beyond the type I/type II model, and base novel therapies on the molecular characteristics of each tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309131PMC
December 2018

Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.

Cancer Res 2019 02 17;79(3):505-517. Epub 2018 Dec 17.

The Center for Bioinformatics and Functional Genomics at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study ( = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of < 7.94 × 10. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely , and . We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-2726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359948PMC
February 2019

Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility.

Genet Med 2019 04 26;21(4):913-922. Epub 2018 Sep 26.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Purpose: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women.

Methods: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing.

Results: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case.

Conclusion: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0277-0DOI Listing
April 2019

Differential and interacting effects of age and sleep restriction on daytime sleepiness and vigilance in adolescence: a longitudinal study.

Sleep 2018 12;41(12)

Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA.

Study Objectives: There is contradictory evidence on whether sleep need decreases across adolescence. We investigated this question longitudinally with a dose-response design to test the effects of varied sleep durations on daytime sleepiness and on vigilance and to test whether these relations change with age across early and mid-adolescence.

Methods: Data from 76 participants who completed at least 2 years of the 3-year study are included in this report. Annually, participants ranging in age from 9.8 to 16.2 years completed three different time in bed (TIB) schedules each consisting of four consecutive nights of 7, 8.5, or 10 hours. Daytime sleepiness (multiple sleep latency test [MSLT]) and vigilance (psychomotor vigilance test [PVT]) were measured on the day following the fourth night of each TIB schedule.

Results: Electroencephalogram (EEG)-measured sleep durations changed linearly with TIB. MSLT-measured daytime sleepiness decreased with longer TIB and increased with age. The TIB and age effects interacted such that the TIB effect decreased with age. PVT performance improved with longer TIB and improved with age, but the benefit that increased TIB conferred on PVT performance did not change with age.

Conclusions: These results seem paradoxical because daytime sleepiness increased but vigilance improved with age. The significant age effect on the relation between TIB and sleepiness compared to the lack of an age effect on the relation between TIB and vigilance performance suggests different rates of maturation in underlying brain systems. We interpret these findings in relation to our model of adolescent brain development driven by synaptic elimination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsy177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191880PMC
December 2018
-->