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Objective To identify the optimal incentive protocol for maximising participation while managing study costs during the Voyage trial.Design Prospective cohort (Voyage trial) of colorectal cancer (CRC) incidence and mortality outcomes in individuals screened with multitarget stool DNA (mt-sDNA) served as the population. A subset was randomised to receive postage stamps as a pre-consent incentive, or as a post-consent incentive after completion of the consent and questionnaire. Descriptive statistics from year 1 are reported.Results During year 1 of the Voyage trial, a total of 600 258 individuals with mt-sDNA orders received at Exact Sciences Laboratories were randomly selected and invited to participate. Of those, 26 429 (4.4%) opted in, 14 365 of whom (54.3%) consented. The opt-in and consent samples were similar to the target population with respect to sex but differed by geographic residence and age (p

IntroductionPopulation-level screening has been shown to reduce the incidence and mortality of colorectal cancer (CRC). Unfortunately, adherence to screening recommendations among eligible US adults remains below national goals. A relatively new non-invasive screening modality, the Food and Drug Administration–approved multi-target stool DNA (mt-sDNA) assay (commercialised as Cologuard), which combines the detection of haemoglobin and DNA abnormalities, has been completed by more than 3 million individuals. Given mt-sDNA’s recent availability, the effectiveness of mt-sDNA screening with respect to CRC incidence and mortality reduction has not yet been established.Methods and analysisThrough an academic–industry collaboration, a prospective cohort study (Voyage) was designed with an initial enrolment target of 150 000 individuals with mt-sDNA ordered by their healthcare provider for CRC screening. Consented participants will be asked to complete a baseline questionnaire to collect sociodemographic and health information. Additional questionnaires will be provided after 1 year, and every 3 years thereafter, to collect data regarding CRC screening follow-up in order to estimate rates of CRC incidence and other health outcomes. Linkage to the National Death Index will be used to estimate mortality rates.Ethics and disseminationThe Voyage study will be conducted in accordance with international guidelines and local regulatory requirements and laws. Data will be stored and retained at Mayo Clinic. Only limited data elements required for research purposes will be transmitted between Mayo Clinic and Exact Sciences Laboratories. Results of the Voyage study will be disseminated through scientific presentations and publications.Trial registration numberNCT04124406.

Colorectal cancer (CRC) is the third leading cause of cancer death in the US. Early detection improves CRC outcomes and multiple options are endorsed for CRC screening; however, adherence remains challenging. Among Medicaid enrollees, the fecal immunochemical test (FIT) is often used for average-risk CRC screening, with suboptimal adherence rates reported (12.3-23.2 %). The navigation-supported (personalized outreach by phone, mail, email and text), at home collection, multi-target stool DNA (mt-sDNA) test represents a relatively recent and broadly accessible option for average-risk CRC screening in Medicaid enrollees. We assessed cross-sectional mt-sDNA adherence in a national sample of Medicaid patients. Data from Exact Sciences Laboratories LLC (ESL; Madison, WI) were retrospectively analyzed. Participants included individuals 45 + years covered by Fee-For-Service (FFS)- or Managed-Medicaid. Primary analysis focused on the 50-74 age cohort and included those with valid mt-sDNA orders between January 1-December 31, 2018. Data from 25,794 individuals who received valid orders for mt-sDNA were included in analysis (61.2 % women; mean age at order 57.5 years). Overall adherence - completion of an ordered test - was 51.3 %. Adherence was 54.6 % in Managed-Medicaid and 38.9 % in FFS-Medicaid. Adherence by age was: 51.5 % for 50-64 years and 47.7 % for 65-74 years. Mt-sDNA tests ordered by gastroenterologists had higher adherence (60.5 %) compared with primary care clinicians (51.3 %). These data from a large, national sample of Medicaid-insured patients substantiate mt-sDNA testing as a viable patient-supported, home-based option to improve average-risk CRC screening participation in Medicaid enrollees., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Polycystic kidney disease (PKD) accounts for approximately 15% of kidney transplants, but long-term outcomes in patients with PKD who have received a kidney transplant are not well understood., Methods: In primary recipients of kidney transplants at our center (1994-2014), we compared outcomes of underlying PKD ( N =619) with other native diseases (non-PKD, N =4312). Potential factors influencing outcomes in PKD were evaluated using Cox proportional-hazards regression and a rigorous multivariable model., Results: Patients with PKD were older and were less likely to be sensitized or to experience delayed graft function (DGF). Over a median follow-up of 5.6 years, 1256 of all recipients experienced death-censored graft failure (DCGF; 115 patients with PKD) and 1617 died (154 patients with PKD). After adjustment for demographic, dialysis, comorbid disease, surgical, and immunologic variables, patients with PKD had a lower risk of DCGF (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.57 to 0.93; P =0.01) and death (aHR, 0.62; 95% CI, 0.51 to 0.75; P <0.001). In our multiadjusted model, calcineurin-inhibitor (CNI) use was associated with lower risk of DCGF (aHR, 0.45; 95% CI, 0.26 to 0.76; P =0.003), whereas HLA mismatch of five to six antigens (aHR, 2.1; 95% CI, 1.2 to 3.64; P =0.009) was associated with higher likelihood of DCGF. Notably, both pretransplant coronary artery disease (CAD) and higher BMI were associated with increased risk of death (CAD, aHR, 2.5; 95% CI, 1.69 to 3.71; P <0.001; per 1 kg/m 2 higher BMI, aHR, 1.07; 95% CI, 1.04 to 1.11; P <0.001), DCGF, and acute rejection. Nephrectomy at time of transplant and polycystic liver disease were not associated with DCGF/death. Incidence of post-transplant diabetes mellitus was similar between PKD and non-PKD cohorts., Conclusions: Recipients with PKD have better long-term graft and patient survival than those with non-PKD. Standard practices of CNI use and promoting HLA match are beneficial in PKD and should continue to be promoted. Further prospective studies investigating the potential benefits of CNI use and medical/surgical interventions to address CAD and the immunologic challenges of obesity are needed., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2021&#95;02&#95;25&#95;KID0001182019.mp3., Competing Interests: S. Wells reports consultancy for Ethicon Inc. T. Ziemlewicz reports consultancy and research funding with Neuwave and Histosonics. T. Ziemlewicz also has ownership interest in Histotonics.  All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Noninvasive prenatal testing accurately detects trisomy for chromosomes 13, 21, and 18, but has a significantly lower positive predictive value for monosomy X. Discordant monosomy X results are often assumed to be due to maternal mosaicism, usually without maternal follow-up. We describe a case of monosomy X-positive noninvasive prenatal testing that was discordant with the 46,XX results from amniocentesis and postnatal testing. This monosomy X pregnancy doubled the single X chromosome, leading to 45,X/46,XX mosaicism in the placenta and uniparental isodisomy X in the amniotic fluid. Thus, at least some discordant monosomy X results are due to true mosaicism in the pregnancy, which has important implications for clinical outcome and patient counseling., (© 2018 John Wiley & Sons, Ltd.)

Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process., (© 2017 Wiley Periodicals, Inc.)

Purpose: Precision oncology develops and implements evidence-based personalized therapies that are based on specific genetic targets within each tumor. However, a major challenge that remains is the provision of a standardized, up-to-date, and evidenced-based precision medicine initiative across a geographic region., Materials and Methods: We developed a statewide molecular tumor board that integrates academic and community oncology practices. The Precision Medicine Molecular Tumor Board (PMMTB) has three components: a biweekly Web-based teleconference tumor board meeting provided as a free clinical service, an observational research registry, and a monthly journal club to establish and revise evidence-based guidelines for off-label therapies. The PMMTB allows for flexible and rapid implementation of treatment, uniformity in practice, and the ability to track outcomes., Results: We describe the implementation of the PMMTB and its first year of activity. Seventy-seven patient cases were presented, 48 were enrolled in a registry, and 38 had recommendations and clinical follow-up. The 38 subjects had diverse solid tumors (lung, 45%; GI, 21%; breast, 13%; other, 21%). Of these subjects, targeted therapy was recommended for 32 (84%). Clinical trials were identified for 24 subjects (63%), and nontrial targeted medicines for 16 (42%). Nine subjects (28%) received recommended therapy with a response rate of 17% (one of six) and a clinical benefit rate (partial response + stable disease) of 38% (three of eight). Although clinical trials often were identified, patients rarely enrolled., Conclusion: The PMMTB provides a model for a regional molecular tumor board with clinical utility. This work highlights the need for outcome registries and improved access to clinical trials to pragmatically implement precision oncology., Competing Interests: Implementation and Clinical Utility of an Integrated Academic-Community Regional Molecular Tumor BoardThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.Mark E. BurkardResearch Funding: Pfizer, AbbVie, Genentech Consulting or Advisory Role: Pointcare GenomicsDustin A. DemingNo relationship to discloseBenjamin M. ParsonsHonoraria: Amgen, CelgeneParaic A. KennyNo relationship to discloseMarissa R. SchuhNo relationship to discloseTiciana LealConsulting or Advisory Role: Genentech, AriadNataliya UbohaNo relationship to discloseJoshua M. LangStock and Other Ownership Interests: Salus DiscoveryMichael A. ThompsonNo relationship to discloseRuth WarrenNo relationship to discloseJordan BaumanNo relationship to discloseMary S. MablyNo relationship to discloseJennifer LaffinNo relationship to discloseCatherine R. PaschalNo relationship to discloseAngela M. LagerNo relationship to discloseKristy LeeNo relationship to discloseKristina A. MatkowskyjNo relationship to discloseDarya G. BuehlerNo relationship to discloseWilliam M. RehrauerNo relationship to discloseJill KolesarNo relationship to disclose, (© 2017 by American Society of Clinical Oncology.)

Background: Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade and stage. However, previous reports have not shown how CA affects cellular differentiation and clinical outcomes in breast cancer., Methods: We analyzed centrosomes by immunofluorescence and compared to ploidy and chromosomal instability (CIN) as assessed by 6-chromosome FISH in a cohort of 362 breast cancers with median clinical follow-up of 8.4 years. Centrosomes were recognized by immunofluorescence using antibodies for pericentriolar material (PCM; pericentrin) and centrioles (polyglutamylated tubulin). CA was experimentally induced in cell culture by overexpression of polo-like kinase 4 (PLK4)., Results: CA is associated with reduced all-cause and breast cancer-specific overall survival and recurrence-free survival. CA correlates strongly with high-risk subtypes (e.g. triple negative) and higher stage and grade, and the prognostic nature of CA can be explained largely by these factors. A strong correlation between CA and high tumor ploidy demonstrates that chromosome and centrosome doubling often occur in concert. CA is proposed to be a method of inducing CIN via aberrant mitotic cell divisions; consonant with this, we observed a strong correlation between CA and CIN in breast cancers. However, some CA tumors had low levels of CIN, indicating that protective mechanisms are at play, such as centrosome clustering during mitosis. Intriguingly, some high-risk tumors have more acentriolar centrosomes, suggesting PCM fragmentation as another mechanism of CA. In vitro induction of CA in two non-transformed human cell lines (MCF10A and RPE) demonstrated that CA induces a de-differentiated cellular state and features of high-grade malignancy, supporting the idea that CA intrinsically causes high-grade tumors., Conclusions: CA is associated with deleterious clinical factors and outcomes in breast cancer. Cell doubling events are the most prevalent causes of CA in cancer, although PCM fragmentation may be a secondary cause. CA promotes high-risk breast cancer in part by inducing high-grade features. These findings highlight the importance of centrosome aberrations in the biology of human breast cancer.

MECP2 duplication syndrome, originally described in 2005, is an X-linked neurodevelopmental disorder comprising infantile hypotonia, severe to profound intellectual disability, autism or autistic-like features, spasticity, along with a variety of additional features that are not always clinically apparent. The syndrome is due to a duplication (or triplication) of the gene methyl CpG binding protein 2 (MECP2). To date, the disorder has been described almost exclusively in males. Female carriers of the duplication are thought to have no or mild phenotypic features. Recently, a phenotype for females began emerging. We describe a family with ∼290 kb duplication of Xq28 region that includes the MECP2 gene where the proposita and affected family members are female. Twin sisters, presumed identical, presented early with developmental delay, and seizures. Evaluation of the proposita at 25 years of age included microarray comparative genomic hybridization (aCGH) which revealed the MECP2 gene duplication. The same duplication was found in the proposita's sister, who is more severely affected, and the proband's mother who has mild intellectual disability and depression. X-chromosome inactivation studies showed significant skewing in the mother, but was uninformative in the twin sisters. We propose that the MECP2 duplication caused for the phenotype of the proband and her sister. These findings support evidence for varied severity in some females with MECP2 duplications., (© 2014 Wiley Periodicals, Inc.)

Aim: To assess the validity and potential clinical utility of evaluating MYC expression by immunohistochemistry (IHC) in mantle cell lymphoma (MCL)., Methods and Results: MYC IHC was scored on a tissue microarray containing 62 MCLs and 29 controls by two pathologists. Inter-observer correlation was high (intra-class correlation of 0.98). MYC IHC scores correlated with MYC expression (Spearman's rank correlation 0.69, P < 0.0001) and weakly with Ki67 proliferation index (Spearman's rank correlation 0.30, P = 0.03). Six blastic MCLs did not have higher mean MYC IHC scores or MYC mRNA expression than non-blastic MCLs. None of 57 cases assessed, including all of the blastic cases, showed MYC rearrangement by fluorescence in-situ hybridization. Multivariate analysis with backward selection from potential predictors including age, lactate dehydrogenase, leukocyte count, MIPI score, ECOG performance status, blastic morphology and Ki67 index showed that MYC IHC score is an independent predictor of progression-free survival (hazard ratio 2.34, 95% CI 1.42-3.88, P = 0.0009) and overall survival (hazard ratio 1.90, 95% CI 1.05-3.43, P = 0.034)., Conclusions: We show that a new monoclonal anti-MYC antibody can enable accurate and reproducible visual assessment of MYC expression that is independently predictive of clinical outcomes in MCL., (© 2013 John Wiley & Sons Ltd.)

Background: Population screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US., Methods: Blood spot screening of 14,207 newborns (7,312 males and 6,895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach., Results: The prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats)., Conclusions: The presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported.

This study investigated the underlying chromosomal abnormalities of testicular failure using molecular cytogenetic analysis. We report 2 cases of rare genetic anomalies that resulted in hypogonadism. The first patient presented with severe hypogonadism. Chromosome analysis revealed a mosaic 46,X,r(Y) (p11.3q11.23)/45,X karyotype, with a ring Y chromosome. A Y chromosome microdeletion assay showed a deletion in the azoospermia factor a region. The second patient presented with infertility and nonobstructive azoospermia. Cytogenetic and fluorescent in situ hybridization analysis revealed a 47,XY,+mar.ish i(15) (D15Z1++,SNRPN2,PML2) karyotype, with a small supernumerary chromosome derived from chromosome 15. These results emphasize the need for molecular cytogenetic evaluation in patients with testicular failure before using advanced reproductive techniques.

Development and implementation of high-density DNA arrays demonstrated the important role of copy number changes on the X chromosome in the etiology of developmental delay and mental retardation (MR). We describe two unrelated patients with developmental delay due to similar interstitial duplications at Xp21-p22. The first patient is a 6-month-old male with multiple affected family members including many females. The second patient is a 5-year-old adopted female. In both patients, chromosome analysis and array comparative genomic hybridization (aCGH) showed duplications of overlapping regions at Xp21-p22. The duplicated segments contain numerous genes associated with MR, including AP1S2, NHS, CDKL5, RPS6KA3, SMS, and ARX. Except for developmental delay, there is little phenotypic overlap between the male and the female patient. Additionally, the female patient and affected female relatives of the male patient have variable severities of cognitive impairment, likely due to different X-inactivation patterns and effects of other, nonduplicated genes important for normal development. These cases illustrate that increased gene dosage of X-linked MR genes lead to cognitive impairment. Precise delineation of chromosome rearrangements by aCGH and identification of genes within duplicated segments helped in establishing genotype-phenotype correlations for each of our patients, in comparing them to each other, as well as with previously reported cases of Xp21-p22 duplications. However, we show that even with detailed molecular characterization, phenotype prediction remains challenging in patients with structural abnormalities of the X chromosome., ((c) 2010 Wiley-Liss, Inc.)

This study examined the utility of array-based comparative genomic hybridization (aCGH) in detecting genetic abnormalities associated with late pregnancy loss. Comparisons were made with classic cytogenetics to test whether aCGH represents a superior methodology for the clinical evaluation of stillbirth. Stillborn infants were selected for aCGH testing from the Wisconsin Stillbirth Service Program (WiSSP) database and tissue bank, based on abnormal clinical findings (presence of at least two abnormalities of two different organs or parts of the body). aCGH analysis was successfully completed in 15 cases which met the clinical criteria and for which sufficient amount of high quality DNA was recovered from archival material. The testing was performed using commercially available 1 Mb BAC arrays. Among 15 tested stillborns, aCGH detected two abnormalities (trisomy 21 and an unbalanced translocation between chromosomes 3 and 10), for an overall detection rate of 13% in stillborns with malformations who had normal or unobtainable cytogenetic results. This preliminary study supports the clinical value of aCGH testing in diagnostic evaluation of stillborns with congenital anomalies., (Copyright 2009 Wiley-Liss, Inc.)