Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

OBJECTIVE: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis. DESIGN: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857). SETTING: North-East London Cancer Network (NELCN) population. POPULATION/SAMPLE: Women with high-grade non-mucinous epithelial OC. METHODS: A more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre-existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken. MAIN OUTCOME MEASURES: Satisfaction, readability, understanding, emotional well-being and preference for long/short DA. RESULTS: The mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision-making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between 'short' and 'long' DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165-1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065-0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017-0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA. CONCLUSIONS: A longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

Probing excited state 1Hα chemical shifts in intrinsically disordered proteins with a triple resonance-based CEST experiment: Application to a disorder-to-order switch.

Over 40% of eukaryotic proteomes and 15% of bacterial proteomes are predicted to be intrinsically disordered based on their amino acid sequence. Intrinsically disordered proteins (IDPs) exist as heterogeneous ensembles of interconverting conformations and pose a challenge to the structure-function paradigm by apparently functioning without possessing stable structural elements. IDPs play a prominent role in biological processes involving extensive intermolecular interaction networks and their inherently dynamic nature facilitates their promiscuous interaction with multiple structurally diverse partner molecules. NMR spectroscopy has made pivotal contributions to our understanding of IDPs because of its unique ability to characterize heterogeneity at atomic resolution. NMR methods such as Chemical Exchange Saturation Transfer (CEST) and relaxation dispersion have enabled the detection of 'invisible' excited states in biomolecules which are transiently and sparsely populated, yet central for function. Here, we develop a 1Hα CEST pulse sequence which overcomes the resonance overlap problem in the 1Hα-13Cα plane of IDPs by taking advantage of the superior resolution in the 1H-15N correlation spectrum. In this sequence, magnetization is transferred after 1H CEST using a triple resonance coherence transfer pathway from 1Hα (i) to 1HN(i + 1) during which the 15N(t1) and 1HN(t2) are frequency labelled. This approach is integrated with spin state-selective CEST for eliminating spurious dips in CEST profiles resulting from dipolar cross-relaxation. We apply this sequence to determine the excited state 1Hα chemical shifts of the intrinsically disordered DNA binding domain (CytRN) of the bacterial cytidine repressor (CytR), which transiently acquires a functional globally folded conformation. The structure of the excited state, calculated using 1Hα chemical shifts in conjunction with other excited state NMR restraints, is a three-helix bundle incorporating a helix-turn-helix motif that is vital for binding DNA.

Population assessment of the Endangered Kashmir Gray Langur (Semnopithecus ajax, Pocock 1928) using the double-observer method.

Primates are among the most threatened taxa globally, therefore, there is a need to estimate and monitor their populations. Kashmir Gray Langur Semnopithecus ajax is an endangered species for which there is no population estimate. We used double-observer method to estimate its population size in the Kashmir region of North-Western Himalaya. We walked 1284 km across 31 survey blocks spanning all three divisions of Kashmir viz., North, Central, and South Kashmir, covering an area of 411 km2. We counted a minimum of 1367 individual langurs from 27 groups. The detection probability for observer 1 (0.719) and observer 2 (0.656) resulted in a population estimate of 1496 (95% confidence interval [CI] 1367-1899) across 30 groups (with a mean group size of 51), giving a density estimate of 3.64 (3.33-4.62) langurs/km². We found double-observer surveys to be suitable for the population estimation of langurs, and we make recommendations on how to effectively conduct primate surveys, especially in mountainous ecosystems. Our records extend the species distribution range beyond stated by the International Union for Conservation of Nature. Our findings also highlight that the Kashmir Himalaya is a stronghold of the species, where conservation efforts should focus.

Range restricted old and young lineages show the southern Western Ghats to be both a museum and a cradle of diversity for woody plants.

The Western Ghats (WG) mountain chain is a global biodiversity hotspot with high diversity and endemicity of woody plants. The latitudinal breadth of the WG offers an opportunity to determine the evolutionary drivers of latitudinal diversity patterns. We examined the spatial patterns of evolutionary diversity using complementary phylogenetic diversity and endemism measures. To examine if different regions of the WG serve as a museum or cradle of evolutionary diversity, we examined the distribution of 470 species based on distribution modelling and occurrence locations across the entire region. In accordance with the expectation, we found that the southern WG is both a museum and cradle of woody plant evolutionary diversity, as a higher proportion of both old and young evolutionary lineages are restricted to the southern WG. The diversity gradient is likely driven by high geo-climatic stability in the south and phylogenetic niche conservatism for moist and aseasonal sites. This is corroborated by persistent lineage nestedness at almost all evolutionary depths (10-135 million years), and a strong correlation of evolutionary diversity with drought seasonality, precipitation and topographic heterogeneity. Our results highlight the global value of the WG, demonstrating, in particular, the importance of protecting the southern WG-an engine of plant diversification and persistence.

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

Expanding the phenotype of TAB2 variants and literature review.

TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome sequencing. Eight individuals had de novo variants, the other six individuals were found to have maternally inherited, or likely maternally inherited, variants. Five individuals from the same family were identified following cardiac disease gene panel in the proband and subsequent targeted familial gene sequencing. The clinical features of this cohort were compared to the existing literature. Common clinical features include distinctive facial features, growth abnormalities, joint hypermobility, hypotonia, and developmental delay. Newly identified features included feeding difficulties, sleep problems, visual problems, genitourinary abnormality, and other anatomical variations. Here we report 14 new individuals, including novel TAB2 variants, in order to expand the emerging syndromic clinical phenotype and provide further genotype-phenotype correlation.

Mortality Prediction in the ICU: The Daunting Task of Predicting the Unpredictable.

How to cite this article: Kumar AAK. Mortality Prediction in the ICU: The Daunting Task of Predicting the Unpredictable. Indian J Crit Care Med 2022;26(1):13-14.

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

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect.

The SLC12 gene family consists of SLC12A1-SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16-18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.

Characterizing Post-Translational Modifications and Their Effects on Protein Conformation Using NMR Spectroscopy.

The diversity of the cellular proteome substantially exceeds the number of genes coded by the DNA of an organism because one or more residues in a majority of eukaryotic proteins are post-translationally modified (PTM) by the covalent conjugation of specific chemical groups. We now know that PTMs alter protein conformation and function in ways that are not entirely understood at the molecular level. NMR spectroscopy has been particularly successful as an analytical tool in elucidating the themes underlying the structural role of PTMs. In this Perspective, we focus on the NMR-based characterization of three abundant PTMs: phosphorylation, acetylation, and glycosylation. We detail NMR methods that have found success in detecting these modifications at a site-specific level. We also highlight NMR studies that have mapped the conformational changes ensuing from these PTMs as well as evaluated their relation to function. The NMR toolbox is expanding rapidly with experiments available to probe not only the average structure of biomolecules but also how this structure changes with time on time scales ranging from picoseconds to seconds. The atomic resolution insights into the biomolecular structure, dynamics, and mechanism accessible from NMR spectroscopy ensure that NMR will continue to be at the forefront of research in the structural biology of PTMs.

Detection of Gap and Modulations: Auditory Temporal Resolution Deficits in Adults Who Stutter.

BACKGROUND: Recent models of speech production suggest a link between speech production and perception. Persons with stuttering are known to have deficits in sensorimotor timing and exhibit auditory processing problems. Most of the earlier studies have focused on assessing temporal ordering in adults who stutter (AWS), but limited attempts have been made to document temporal resolution abilities in AWS. METHODS: A group of 16 AWS and 16 age- and gender-matched adults who do not stutter (AWNS) were recruited for the study. Temporal resolution abilities were assessed using the Gap Detection Test and temporal modulation transfer function (TMTF). RESULTS: The results revealed significant differences in TMTF between AWS and AWNS, but no differences were found in the gap detection thresholds. CONCLUSIONS: Results suggest that the sensory representations of the temporal modulations are compromised in AWS, which may contribute to the programming of rhythmic movements during speech planning.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

Outcomes of annual surveillance imaging in an adult and paediatric cohort of succinate dehydrogenase B mutation carriers.

OBJECTIVE: For 'asymptomatic carriers' of the succinate dehydrogenase subunit B (SDHB) gene mutations, there is currently no consensus as to the appropriate modality or frequency of surveillance imaging. We present the results of a surveillance programme of SDHB mutation carriers. DESIGN: Review of clinical outcomes of a surveillance regimen in patients identified to have an SDHB gene mutation, based on annual MRI, in a single UK tertiary referral centre. PATIENTS: A total of 92 patients were identified with an SDHB gene mutation. a total of 27 index patients presented with symptoms, and 65 patients were identified as asymptomatic carriers. MEASUREMENTS: Annual MRI of the abdomen, with alternate year MRI of the neck, thorax and pelvis. Presence of an SDHB-related tumour included paraganglioma (PGL), phaeochromocytoma (PCC), renal cell carcinoma (RCC) and gastrointestinal stromal tumour (GIST). RESULTS: A total of 43 PGLs, eight PCCs and one RCC occurred in the 27 index patients (23 solitary, four synchronous, five metachronous). A further 15 SDHB-related tumours (11 PGLs, three RCCs, one GIST) were identified in the asymptomatic carriers on surveillance screening (25% of screened carriers): 10 on the first surveillance imaging and five on subsequent imaging 2-6 years later. A total of 11 patients had malignant disease. CONCLUSIONS: SDHB-related tumours are picked up as early as 2 years after initial negative surveillance scan. We believe the high malignancy rate and early identification rate of tumours justifies the use of 1-2 yearly imaging protocols and MRI-based imaging could form the mainstay of surveillance in this patient group thereby minimizing radiation exposure.

High voltage generation from lead-free magnetoelectric coaxial nanotube arrays and their applications in nano energy harvesters.

Harvesting energy from surrounding vibrations and developing self-powered portable devices for wireless and mobile electronics have recently become popular. Here the authors demonstrate the synthesis of piezoelectric energy harvesters based on nanotube arrays by a wet chemical route, which requires no sophisticated instruments. The energy harvester gives an output voltage of 400 mV. Harvesting energy from a sinusoidal magnetic field is another interesting phenomenon for which the authors fabricated a magnetoelectric energy harvester based on piezoelectric-magnetostrictive coaxial nanotube arrays. Piezoelectric K0.5Na0.5NbO3 (KNN) is fabricated as the shell and magnetostrictive CoFe2O4 (CFO) as the core of the composite coaxial nanotubes. The delivered voltages are as high as 300 mV at 500 Hz and at a weak ac magnetic field of 100 Oe. Further tailoring of the thickness of the piezoelectric and magnetic layers can enhance the output voltage by several orders. Easy, single-step wet chemical synthesis enhances the industrial upscaling potential of these nanotubes as energy harvesters. In view of the excellent properties reported here, the lead-free piezoelectric component (KNN) in this nanocomposite should be explored for eco-friendly piezoelectric as well as magnetoelectric power generators in nanoelectromechanical systems (NEMS).

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations.

BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. SECONDARY OUTCOMES: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. RESULTS: 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). CONCLUSIONS: DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. TRIAL REGISTRATION NUMBER: ISRCTN 73338115.

Gene-gene interactions in breast cancer susceptibility.

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.

AIP mutation in pituitary adenomas in the 18th century and today.

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.