Publications by authors named "Dawn C Allain"

21 Publications

  • Page 1 of 1

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Am J Med Genet A 2021 Mar 30. Epub 2021 Mar 30.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
March 2021

Age of onset and behavioral manifestations in Huntington's disease: An Enroll-HD cohort analysis.

Clin Genet 2021 Jan 16;99(1):133-142. Epub 2020 Oct 16.

Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll-HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid-adult onset (30-59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid-adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one-year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one-year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals.
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http://dx.doi.org/10.1111/cge.13857DOI Listing
January 2021

MicroRNA Expression Profiling of Cutaneous Squamous Cell Carcinomas Arising in Different Sites.

Otolaryngol Head Neck Surg 2020 09 19;163(3):538-545. Epub 2020 May 19.

Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Objective: To examine the microRNA (miRNA) expression profile of cutaneous squamous cell carcinoma (cSCC) tumors from aggressive head and neck locations compared with nonaggressive anatomic sites and normal controls.

Study Design: Retrospective analysis of miRNA expression.

Setting: Tertiary care center.

Subjects And Methods: Tissue samples were collected from 3 anatomic regions: aggressive head and neck sites (ie, ears/lip), nonaggressive locations (ie, extremities/trunk), and adjacent normal skin. RNA was isolated from tissue cores of 45 samples (18 aggressive sites, 15 nonaggressive sites, and 12 normal-adjacent skin). miRNA expression analysis was completed for approximately 800 miRNAs using the NanoString nCounter panel. Five candidate miRNAs were selected for validation. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the original samples plus 30 additional tissue samples (7 aggressive sites, 14 nonaggressive sites, and 9 normal-adjacent skin).

Results: Five candidate miRNAs with significant differences in miRNA expression ( < 0 ≤ .001) from discovery samples were selected: , and . Relative expression for these miRNAs using qRT-PCR in the new sample set did not reveal any significant differences using 1-way analysis of variance. When sets were combined, showed increased expression in aggressive tumors relative to nonaggressive tumors ( = .009), but no others reached statistical significance.

Conclusion: cSCC behaves more aggressively when originating from specific anatomical subsites of the head and neck. Of 5 miRNAs evaluated, only showed significantly higher expression in tumors from aggressive sites relative to nonaggressive sites. Larger sample sizes are needed to evaluate other miRNAs.
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http://dx.doi.org/10.1177/0194599820918855DOI Listing
September 2020

Maternal age at delivery and fertility of the next generation.

Paediatr Perinat Epidemiol 2020 11 9;34(6):629-636. Epub 2020 Mar 9.

Genetic Counseling Graduate Program, Department of Internal Medicine, Division of Human Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States.

Background: While most known causes of infertility relate to the health of the woman and/or her partner, questions have been raised regarding the possible contributions of transgenerational or epigenetic factors.

Objective: The goal of this hypothesis-generating work was to examine whether Generation 1's (G1's) age at the delivery of G2 (Generation 2) was associated with G2's fertility in later life.

Methods: We conducted a retrospective cohort study of women (G2s) recruited online in 2016. A questionnaire queried G2s regarding demographics and fertility. The primary exposure was G1's age at G2's birth. Outcome measures included the following: 12-month infertility, time to pregnancy, and childlessness. The adjusted relative risk (RR) of G2 infertility and childlessness by G1 age at G2's birth was estimated through a modified Poisson regression approach. The fecundity odds ratio (FOR) for the association between G1's age at G2 birth and time to pregnancy for G2 was estimated by discrete-time survival models, with complementary log-log link.

Results: A total of 2,854 women enrolled. We found no association between G1 age at G2's birth and G2 infertility. Being born to a G1 aged 15-19 years was associated with a longer time to pregnancy for G2 (FOR 0.84, 95% confidence interval 0.72, 0.99), relative to being born to a G1 aged 20-24 years. We observed the suggestion of a possible increased risk of childlessness among G2s born to older G1s, but the estimate was imprecise.

Conclusions: While being born to a G1 who was 15-19 years old was associated with an increase in G2 time to pregnancy, we found no association between G1 age at G2's birth and infertility and only the suggestion of a modest association with childlessness. These data suggest a possible subtle effect of G1 age at G2's birth on G2 fertility, which warrants further study.
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http://dx.doi.org/10.1111/ppe.12666DOI Listing
November 2020

Alzheimer's disease development in adults with Down syndrome: Caregivers' perspectives.

Am J Med Genet A 2020 01 22;182(1):104-114. Epub 2019 Oct 22.

Genetic Counseling Graduate Program, Division of Human Genetics, The Ohio State University, Columbus, Ohio.

Research about Alzheimer's disease (AD) in individuals with Down syndrome (DS) has predominantly focused on the underlying genetics and neuropathology. Few studies have addressed how AD risk impacts caregivers of adults with DS. This study aimed to explore the perceived impact of AD development in adults with DS on caregivers by assessing caregiver knowledge, concerns, effect on personal life, and resource utilization via a 40-question (maximum) online survey. Survey distribution by four DS organizations and two DS clinics resulted in 89 caregiver respondents. Only 28 caregivers correctly answered all three AD knowledge questions. Caregivers gave an average AD concern rating of 5.30 (moderately concerned) and an average impact of possible diagnosis rating of 6.28 (very strong impact), which had a significant negative correlation with the age of the adult with DS (p = .009). Only 33% of caregivers reported utilization of resources to gain more information about the AD and DS association, with low levels of perceived usefulness. Our data reveal caregivers' misconceptions about AD development in DS, underutilization of available resources, and substantial concerns and perceived impacts surrounding a possible AD diagnosis. This study lays the foundation for how the medical community can better serve caregivers of aging adults with DS.
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http://dx.doi.org/10.1002/ajmg.a.61390DOI Listing
January 2020

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

J Natl Cancer Inst 2018 09;110(9):967-974

Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population.

Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database.

Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele.

Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.
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http://dx.doi.org/10.1093/jnci/djy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924PMC
September 2018

An assessment of health, social, communication, and daily living skills of adults with Down syndrome.

Am J Med Genet A 2018 06 25;176(6):1389-1397. Epub 2018 Apr 25.

Department of Genetics and Genome Sciences, University Hospitals Case Medical Center, Cleveland, Ohio.

Adults with Down syndrome (DS) are surviving longer, yet data delineating life skills are lacking. As providers are encouraged to provide a "balanced" description of DS to family members/caregivers, more quantitative data are required to accurately describe the abilities and potential of adults with DS. This study assessed health, social, communication, and daily living skills of adults with DS to describe the range of abilities and to show how increasing age contributes to functional abilities. Caregivers of an adult with DS 20 years of age or older participated in an online questionnaire. Descriptive statistics and scores from scales assessed relationships between the number of health issues reported and functional abilities, and how the abilities changed as age increased. Of 188 participants, 157 completed the survey with partial results included. Communication, independence, and social activity scores were compared to the number of congenital and non-congenital health issues reported. Linear regression results showed those with more health issues were significantly less likely to be independent and social. However, only current health issues affected communication skills. No significant correlation occurred between the number of congenital abnormalities and scores for independence/life skills as an adult. T-test by age group found decreasing abilities after 40 years of age. In conclusion, quantitative data and information from this study is beneficial for providers in order to describe the potential for an individual with DS and to assist caregivers to plan accordingly for the future of their adult with DS.
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http://dx.doi.org/10.1002/ajmg.a.38721DOI Listing
June 2018

Patients with sporadic and familial amyotrophic lateral sclerosis found value in genetic testing.

Mol Genet Genomic Med 2018 03 20;6(2):224-229. Epub 2017 Dec 20.

Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a genetic disease. There is no consensus, however, as to the role of genetic testing in the care of the ALS patient.

Methods: We conducted a survey to study patient access, attitudes, and experience with ALS genetic testing among patients enrolled in a US ALS registry.

Results: Among 449 survey respondents, 156 (34.7%) were offered testing and 105 of 156 (67.3%) completed testing. The majority of respondents with familial ALS (fALS) (31/45, 68.9%) were offered testing, while a minority of respondents with sporadic ALS (sALS) (111/404, 27.5%) were offered testing (p = .00001). Comparison of mean test experience scores between groups revealed that respondents with fALS were no more likely to report a favorable experience with genetic testing than those with sALS (p = .51). Respondents who saw a genetic counselor did not have significantly different test experience scores, compared to those who did not (p = .14). In addition, no differences in test experience scores were observed between those who received positive or negative genetic test results (p = .98).

Conclusion: These data indicate that patients with ALS found value in clinical genetic testing.
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http://dx.doi.org/10.1002/mgg3.360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902388PMC
March 2018

At the Heart of the Pregnancy: What Prenatal and Cardiovascular Genetic Counselors Need to Know about Maternal Heart Disease.

J Genet Couns 2017 Aug 10;26(4):669-688. Epub 2017 Mar 10.

Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.

In the last decade, an increasing number of cardiac conditions have been shown to have a genetic basis. Cardiovascular genetic counseling has emerged as a subspecialty aiming to identify unaffected at-risk individuals. An important sector of this at-risk population also includes expectant mothers, in whom unique clinical challenges may arise. Genetic counselors, especially those in cardiovascular and prenatal settings, have an opportunity to identify and assist women who may benefit from cardiovascular care during pregnancy. This paper provides basic management and genetic evaluation principles for affected women, as well as guidance on identifying those who are at risk. We provide considerations for cardiac surveillance in pregnancy and the post-partum period. Finally, key psychosocial issues that appraise how to best provide support to at risk women as they make informed decisions are discussed. We propose that a team approach including cardiology, maternal fetal medicine, and genetic counseling best serves this patient population. Ongoing questions addressing an evidence based approach to cardiovascular genetic conditions in pregnancy still remain. Thus, well-designed research protocols are essential to mark progress in this area.
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http://dx.doi.org/10.1007/s10897-017-0081-zDOI Listing
August 2017

Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors.

Cancer 2017 04 1;123(7):1184-1193. Epub 2016 Dec 1.

Department of Cancer Biology and Genetics, The Ohio State Wexner Medical Center, The Ohio State University, Columbus, Ohio.

Background: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease.

Methods: Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs.

Results: The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P<.0001).

Conclusions: These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360561PMC
April 2017

Patients with Amyotrophic Lateral Sclerosis Have High Interest in and Limited Access to Genetic Testing.

J Genet Couns 2017 Jun 20;26(3):604-611. Epub 2016 Oct 20.

Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

Although genetic testing for amyotrophic lateral sclerosis (ALS) is widely available, it is unknown what proportion of patients with ALS have access to genetic counseling and testing, and patient attitudes towards ALS genetic testing have not been studied. We conducted a national survey of ALS patients enrolled in the Agency for Toxic Substances and Disease Registry, which consisted of multiple choice questions and two 12 item Likert scale series assessing respondents' experience with and attitude toward genetic testing. The survey had an 8 % response rate, with 449 completed responses. Genetic testing was offered to 33.4 % and completed by 67.1 % of those offered. A minority of respondents (12.5 %) saw a genetic counselor, and were much more likely to be offered genetic testing (p = 0.0001). Respondents with a family history of ALS (8.4 %) were more likely to be offered testing (p = 0.0001) and complete testing (p = 0.05). Respondents with a family history of ALS were more likely to report a favorable attitude towards genetic testing (p = 0.0003), as were respondents who saw a genetic counselor (p = 0.02). The majority of respondents (82.7 %) felt that genetic testing should be offered to all patients with ALS. Our results indicate that ALS patients may have limited access to genetic testing, but perceive benefit from this service. Development of practice guidelines for genetic testing in ALS, to include the routine offer of genetic counseling, may result in broader and more consistent access to these services.
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http://dx.doi.org/10.1007/s10897-016-0034-yDOI Listing
June 2017

Non-genetic health professionals' attitude towards, knowledge of and skills in discussing and ordering genetic testing for hereditary cancer.

Fam Cancer 2016 Apr;15(2):341-50

Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Non-genetic health professionals (NGHPs) have insufficient knowledge of cancer genetics, express educational needs and are unprepared to counsel their patients regarding their genetic test results. So far, it is unclear how NGHPs perceive their own communication skills. This study was undertaken to gain insight in their perceptions, attitudes and knowledge. Two publically accessible databases were used to invite NGHPs providing cancer genetic services to complete a questionnaire. The survey assessed: sociodemographic attributes, experience in ordering hereditary cancer genetic testing, attitude, knowledge, perception of communication skills (e.g. information giving, decision-making) and educational needs. Of all respondents (N = 49, response rate 11%), most have a positive view of their own information giving (mean = 53.91, range 13-65) and decision making skills (64-77% depending on topic). NGHPs feel responsible for enabling disease and treatment related behavior (89-91%). However, 20-30% reported difficulties managing patients' emotions and did not see management of long-term emotions as their responsibility. Correct answers on knowledge questions ranged between 41 and 96%. Higher knowledge was associated with more confidence in NGHPs' own communication skills (r(s) = .33, p = 0.03). Although NGHPs have a positive view of their communication skills, they perceive more difficulties managing emotions. The association between less confidence in communication skills and lower knowledge level suggests awareness of knowledge gaps affects confidence. NGHPs might benefit from education about managing client emotions. Further research using observation of actual counselling consultations is needed to investigate the skills of this specific group of providers.
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http://dx.doi.org/10.1007/s10689-015-9852-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803807PMC
April 2016

Models of service delivery for cancer genetic risk assessment and counseling.

J Genet Couns 2014 Apr 26;23(2):239-53. Epub 2013 Oct 26.

Center for Molecular Medicine and Genetics, Wayne State University, 540 E. Canfield Street, 2375 Scott Hall, Detroit, MI, 48201, USA,

Increasing awareness of and the potentially concomitant increasing demand for cancer genetic services is driving the need to explore more efficient models of service delivery. The aims of this study were to determine which service delivery models are most commonly used by genetic counselors, assess how often they are used, compare the efficiency of each model as well as impact on access to services, and investigate the perceived benefits and barriers of each. Full members of the NSGC Familial Cancer Special Interest Group who subscribe to its listserv were invited to participate in a web-based survey. Eligible respondents were asked which of ten defined service delivery models they use and specific questions related to aspects of model use. One-hundred ninety-two of the approximately 450 members of the listserv responded (42.7%); 177 (92.2%) had provided clinical service in the last year and were eligible to complete all sections of the survey. The four direct care models most commonly used were the (traditional) face-to-face pre- and post-test model (92.2%), the face-to-face pretest without face-to-face post-test model (86.5%), the post-test counseling only for complex results model (36.2%), and the post test counseling for all results model (18.3%). Those using the face-to-face pretest only, post-test all, and post-test complex models reported seeing more new patients than when they used the traditional model and these differences were statistically significantly. There were no significant differences in appointment wait times or distances traveled by patients when comparing use of the traditional model to the other three models. Respondents recognize that a benefit of using alternative service delivery models is increased access to services; however, some are concerned that this may affect quality of care.
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http://dx.doi.org/10.1007/s10897-013-9655-6DOI Listing
April 2014

Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma.

Int J Cancer 2014 Jan 16;134(1):244-8. Epub 2013 Jul 16.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH; The Ohio State University Comprehensive Cancer Center, Columbus, OH.

More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in ∼10% of cSCC tumors. Here, we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis.
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http://dx.doi.org/10.1002/ijc.28339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831612PMC
January 2014

Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act.

Fam Cancer 2012 Dec;11(4):637-44

Division of Human Genetics, Comprehensive Cancer Center, The Ohio State University, 2001 Polaris Parkway, Columbus, OH 43240, USA.

To examine the awareness and attitudes about the Genetic Information Nondiscrimination Act in individuals who made contact with a Hereditary Breast and Ovarian Cancer Syndrome advocacy group. This is a descriptive study of individuals (n = 1,699) who were invited via email and advertisements to complete an online questionnaire available from August 2009 through December 2010. Response distributions of relevant subgroups were compared using cross tabulation and Chi-squared tests were used. The majority of respondents (69.2 %) had undergone genetic testing (n = 1,156) and 30.2 % had not. Of those who did not undergo genetic testing, the most common reason given for declining testing was cost (28.8 %), followed by concerns about insurance discrimination (19.5 %). More than half (60.5 %) were worried about health insurance discrimination when they first considered genetic testing and 28.6 % were worried about employment discrimination. Slightly more individuals were worried about health insurance discrimination if they had no prior knowledge of GINA. While "cost" was cited most frequently as the reason not to test, "fear of insurance discrimination" was the second most common reason. Knowledge of GINA among consumers is still limited and public education may help promote reduction in fear.
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http://dx.doi.org/10.1007/s10689-012-9564-0DOI Listing
December 2012

Germline variation controls the architecture of somatic alterations in tumors.

PLoS Genet 2010 Sep 23;6(9):e1001136. Epub 2010 Sep 23.

Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, United States of America.

Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value<1x10(-7)), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value=0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles.
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http://dx.doi.org/10.1371/journal.pgen.1001136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944791PMC
September 2010

Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals.

J Invest Dermatol 2009 Dec 25;129(12):2868-74. Epub 2009 Jun 25.

Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA.

Squamous cell carcinoma (SCC) is the second most frequently diagnosed skin cancer. It has a higher incidence in immunosuppressed individuals such as organ transplant recipients and human immunodeficiency virus (HIV) carriers. Recently, a newly described polyoma virus, Merkel cell polyomavirus (MCPyV), was found in Merkel cell carcinoma (MCC), a rare aggressive skin cancer also associated with immunosuppression. We hypothesized that MCPyV would be present in SCCs. To test for the presence of MCPyV in immunocompetent SCC patients, we used PCR primer sets directed against the large T (LT) antigen and VP1 gene of MCPyV. We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied. We did not detect MCPyV in any matched normal blood DNA (0/57), but observed the presence of MCPyV DNA in 1 of 12 normal mouthwash DNAs. All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration. The presence of MCPyV in approximately 15% of SCCs from immunocompetent individuals warrants evaluation of MCPyV as an etiologic agent in the carcinogenesis of SCC.
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http://dx.doi.org/10.1038/jid.2009.183DOI Listing
December 2009

Genetic counseling and testing for common hereditary breast cancer syndromes: a paper from the 2007 William Beaumont hospital symposium on molecular pathology.

Authors:
Dawn C Allain

J Mol Diagn 2008 Sep 7;10(5):383-95. Epub 2008 Aug 7.

Clinical Cancer Genetics Program, Human Cancer Genetics Program, Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA.

Throughout the past 15 years, the identification of several genes associated with hereditary breast cancer has fueled the growth of clinical genetic counseling and testing services. In addition, increased knowledge of the genetic and molecular pathways of the known hereditary breast cancer genes, as well as an increased understanding of the impact of testing on individuals has added to the ability to identify, manage, and provide psychosocial support for mutation carriers. This review provides an overview of the clinical features, cancer risks, causative genes, and management for hereditary breast and ovarian cancer syndrome, Cowden syndrome, and Li-Fraumeni syndrome. This article summarizes the genetic counseling process and genetic test result interpretation, including a review of the key elements involved in the provision of risk assessment and informed consent, as well as a review of the risks, benefits, and limitations of cancer susceptibility genetic testing.
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http://dx.doi.org/10.2353/jmoldx.2008.070161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518733PMC
September 2008

Management options after prophylactic surgeries in women with BRCA mutations: a review.

Cancer Control 2007 Oct;14(4):330-7

Clinical Cancer and Human Cancer Genetics Programs and Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.

Background: Although breast cancer is relatively common, only about 5% of cases are due to inheritance of highly penetrant cancer susceptibility genes. The majority of these are caused by mutations in the BRCA1 and BRCA2 genes, which are also associated with an increased risk of ovarian cancer. Increased surveillance, chemoprevention, and prophylactic surgeries are standard options for the effective medical management of mutation carriers. However, optimal management of female carriers who choose to undergo prophylactic surgeries is still poorly understood.

Methods: The authors provide an overview of the current literature regarding medical management options for women carriers of BRCA1 and BRCA2 gene mutations and the implications for those individuals who have chosen to undergo prophylactic surgeries.

Results: BRCA mutation carriers who opt for prophylactic surgeries are still at risk for development of malignancy, and appropriate monitoring is warranted.

Conclusions: There are limited data on the appropriate medical management for BRCA mutation carriers after prophylactic surgeries. However, a management plan can be extrapolated from the general management recommendations for surveillance and other risk-reducing strategies in BRCA-positive individuals.
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http://dx.doi.org/10.1177/107327480701400403DOI Listing
October 2007

Presidential address 2003: NSGC living life forward.

Authors:
Dawn C Allain

J Genet Couns 2004 Feb;13(1):1-7

Genetic Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA.

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http://dx.doi.org/10.1023/b:jogc.0000013378.49516.4bDOI Listing
February 2004