Cancer Genetic Studies Research Articles

Factors associated with breast cancer genetic knowledge in a local public health district.

e13053Background: Public health (PH) clinics are in the process of optimizing genetic referrals from primary care settings. Adherence to breast cancer genetic screening guidelines depend on patient- and provider-related factors, including knowledge about breast cancer genetics. The objective of this study was to assess factors associated with knowledge about Breast Cancer (BC) genetics among female patients & PH employees across a rural health district. Methods: Cross-sectional study with mixed sampling (convenience & intra stratum systematic randomization) of adult female patients and female PH employees across 12 health clinics in Georgia. Respondents completed a modified, validated BC Genetic Questionnaire (developed from NIH Cancer Genetic Studies Consortium) that assessed socio-demographics, knowledge about BC, interest in genetic screening and Health Belief Model constructs. Factorial analysis of variance and multivariate regression were used compare means & elucidate associations with knowledge sco...

Commentary: Post-GWAS era: What can we do beyond cancer genetic association studies?

Commentary: Post-GWAS era: What can we do beyond cancer genetic association studies?

Turkish Ministry of Health, 2nd Turkish Medical General Assembly Clinical Oncology Study Group Report.

There is an increase in the incidence of cancer, and consequently in mortality rates, both in the world and in Turkey. The increase in the incidence and mortality rate of cancer are more prominent in our country as well as in other developing countries. The aim of this workshop was to determine the current status on prevention, screening, early diagnosis and treatment of cancer in our country, to identify related shortcomings, specify solutions and to share these with health system operators, and to aid in implementation of these systems. Developments on palliative care were also evaluated. The current situation in the practice of clinical oncology, related drawbacks, problems encountered during multidisciplinary approach and their solutions were discussed under several sub-headings during a 3-day meeting organized by the Turkish Ministry of Health (Türkiye Cumhuriyeti Sağlık Bakanlığı-TCSB) with participation of 16 scientists from Turkey and 6 from abroad, and the conclusions were reported. It is expected that the newly established Turkish Health Institutes Association (Türkiye Sağlık Enstitüleri Başkanlığı-TÜSEB) and the National Cancer Institute (Ulusal Kanser Enstitüsü) will provide a new framework in the field of oncology. The current positive findings include the increase in the number of scientists who carry out successful trials in oncology both in Turkey and abroad, the implementation of the national cancer registry program by the Cancer Control Department and the breast cancer registry program by the Turkish Federation of Breast Diseases Societies (Türkiye Meme Hastalıkları Dernekleri Federasyonu-TMHDF), and introduction of Cancer Early Diagnosis, Screening, and Training Centers (Kanser Erken Tanı, Tarama ve Eğitim Merkezi-KETEM) for the application of community-based cancer screening programs. In addition to these, obvious shortcomings related to education, implementation, management and research issues were also determined, and policy and project proposals to address these issues were presented. Collaboration with relevant organizations in the implementation of these studies was supported. Both the incidence and mortality rates of cancer are increasing in Turkey. The widespread deficiencies in population-based screening and in effective treatment lead to an increase in delay in diagnosis and mortality. Despite improvements in data recording, screening and treatment over the last 10 years, extensive, organized, population-based screening programs and fully equipped early diagnosis and treatment centers are required. Enhancement of basic cancer epidemiologic, translational, genetic and molecular research studies is essential in our country. Improvements on pain treatment and palliative care of patients with chronic and terminal cancer are also required.

Approaches to Inactivate Genes in Zebrafish.

Animal models of tumor initiation and tumor progression are essential components toward understanding cancer and designing/validating future therapies. Zebrafish is a powerful model for studying tumorigenesis and has been successfully exploited in drug discovery. According to the zebrafish reference genome, 82 % of disease-associated genes in the Online Mendelian Inheritance in Man (OMIM) database have clear zebrafish orthologues. Using a variety of large-scale random mutagenesis methods developed to date, zebrafish can provide a unique opportunity to identify gene mutations that may be associated with cancer predisposition. On the other hand, newer technologies enabling targeted mutagenesis can facilitate reverse cancer genetic studies and open the door for complex genetic analysis of tumorigenesis. In this chapter, we will describe the various technologies for conducting genome editing in zebrafish with special emphasis on the approaches to inactivate genes.

Abstract 2780: Evaluation of genetic variants in high and moderate-penetrance breast cancer susceptibility genes in East Asians

Abstract Breast cancer is the most common invasive cancer in females worldwide. Over the past 20 years, pathogenic mutations in high-penetrance genes (BRCA1, BRCA2, PTEN and TP3) and moderate-penetrance genes (CHEK2, ATM, BRIP1, PALB2, RAD51C, STK11, CDH1, RAD50, and NBN) have been identified for breast cancer. Most of these germline mutations were discovered in women of European ancestry. In the present study, we aimed to investigate whether there were additional variants in these genes associated with breast cancer among women of Asian ancestry. Genotype data of up to 584 SNPs from the Breast Cancer Association Consortium (BCAC) including 6,269 cases and 6,624 controls and Shanghai Breast Cancer Genetics Study (SBCGS) including 5,768 cases and 5,703 controls were analyzed. Among 18 reported pathogenic mutations included in the dataset, 12 were monomorphic. Rare allele was observed for the remaining 6 mutations and one of them showed a significant association with P value of 0.0096. Among the remaining SNPs that were not previously reported to be pathogenic, 17 SNPs showed nominal association with P<0.05 in the Asian populations. Notably, SNP rs80359065 in the BRCA2 gene showed significant association with OR (95% CI) of 1.46 (1.15-1.84) and P value of 1.8 × 10−3 in the BCAC, and OR (95% CI) of 1.14 (1.03-1.27) and P value of 1.3 × 10−2 in the SBCGS. In the combined data, the OR (95% CI) was 1.23 (1.13-1.32) and the P value reached 7.0 × 10−5, lower than the bonferroni corrected P value (9.1 × 10−5). This SNP has a minor allele frequency (MAF) of 1% in the present study, more prevalent than reported pathogenic mutations. Another variant in the BRCA2 gene, rs80358978, was also associated with breast cancer with P value of 5.8 × 10−3 in the combined dataset. In the BRCA1 gene, three low-frequency variants with MAF<0.1% were associated with breast cancer, including rs8176085, rs799923, and rs1799950 with P values of 8.7 × 10−4, 1.0 × 10−3, and 5.8 × 10−3, respectively. Two common variants with MAF>10% in the RAD50 gene were also associated with breast cancer with P value of 1.0 × 10−3 and 2.1 × 10−3 for rs17772583 and rs2244012, respectively. Our study identified several new risk variants in the BRCA1, BRCA2 and RAD50 genes in relation to breast cancer risk in East Asian women and showed that many of the previously reported pathogenic mutations in the high/moderate penetrance genes of breast cancer are rare in our study population comprising largely sporadic breast cancer patients of East Asian ancestry. Citation Format: Mi-Ryung Han, Xiao-Ou Shu, Qiuyin Cai, Yu-Tang Gao, Ying Zheng, Kyriaki Michailidou, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ji-Yeob Choi, Mikael Hartman, Daehee Kang, Artitaya Lophatananon, Hui Miao, Keitaro Matsuo, Kenneth Muir, Sulee Sangrajrang, Chen-Yang Shen, Soo Hwang Teo, Anna H Wu, Alison M. Dunning, Paul D. P. Pharoah, Douglas F. Easton, Wei Zheng, Jirong Long. Evaluation of genetic variants in high and moderate-penetrance breast cancer susceptibility genes in East Asians. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2780. doi:10.1158/1538-7445.AM2015-2780

Genetic causes of cancer predisposition in children and adolescents.

The acquisition of de novo somatic mutations accounts for approximately 90% of all new cancer diagnoses, while the remaining 10% is due to inherited genetic traits. In this latter category, individuals harbouring germline mutations show a higher likelihood of developing potentially life-threatening cancers, often at a very young age. The study of cancer genetics has profoundly helped our understanding of cancer biology, leading to better characterised malignancies, tailored targeted therapies and the identification of individuals at high risk of cancer diagnosis. This review will discuss examples of cancer syndromes in children, adolescents and young adults, the main underlying gene mutations, and the use of genetic testing to identify gene mutation carriers. Finally, we will describe how gene mutation detection is employed for the life-long management of patients with high susceptibility to cancer, including genetic counselling, increased surveillance, early intervention and use of targeted therapies.

A retrospective observational study of the relationship between single nucleotide polymorphisms associated with the risk of developing colorectal cancer and survival.

BackgroundThere is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined.MethodsAll enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival.ResultsThe linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05–1.22, P = 0.0015).ConclusionThe CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker.

Clinically relevant genetic characterization of prostate tumors: how close are we to the goal?

Substantial efforts are being made in research on the molecular genetic characterization of prostate cancer. The number of fundamental research programs in prostate cancer molecular biology and genetics is overwhelming. However, a significant gap appears to exist between the huge number of studies on the genetic characterization of prostate cancer, which often have limited translation into clinical practice or simply were not conceived to be so translated, and clinical practice. From a clinical point of view, this balance should be urgently shifted towards rapid translation into urological practice. However, prostate cancer is characterized by prominent genetic heterogeneity, which could be a very difficult barrier to overcome. In this review, we discuss the possible clinical applications of scientific data from fundamental studies of prostate cancer genetics, the main problems with the translation of these data to clinics, and future perspectives.

Host genetics of Epstein-Barr virus infection, latency and disease.

Epstein–Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host–EBV interaction. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.

Abstract B12: Recruitment of African American breast cancer pedigrees for The Jewels in Our Genes Study: Recruitment outcomes and sample characteristics

Abstract Background. Few studies have investigated the contribution of inherited genetic variation to breast cancer disparities and fewer have examined whether risk alleles shared in families may contribute to higher risk of aggressive tumors. One barrier is the challenge of effectively recruiting African American families for research. Methods. Using a community-based participatory research (CBPR) orientation, we utilized multi-level methods in an iterative fashion to recruit for a breast cancer genetic linkage study. We recruited affected relative pairs as well as discordant sibling pairs where possible. We analyzed our recruitment yield by method and calculated descriptive statistics for several demographic and clinical characteristics of families selected for genotyping, which includes 281 individuals from 106 pedigrees (197 affecteds, 84 unaffecteds). Results. We recruited 341 African American women (247 with breast cancer and 94 unaffecteds) from 127 families. The top three yields were obtained via collaboration with the Love Army of Women (34% of sample), The National Witness Project (NWP, 29% of sample), and previous epidemiologic studies (24% of sample). Within the set of 106 pedigrees selected for genotyping, 27 pedigrees have one affected relative, 68 pedigrees have 2 affecteds, 10 pedigrees have 3 affecteds, and one pedigree has 6 affecteds. Where adjudicated (n=141, 72%), the mean and median age at diagnosis was 51.6 years (SD 12.0) and 51.6 years, respectively. Affected women were younger at menarche (p=0.002) and more likely to be hysterectomized (p=0.018) compared to unaffected women. According to tumor receptor status, approximately 26% of cases are ER negative, 40% are PR negative, 49% are HER2 negative, and overall 16% are ER/PR/HER2 negative. Conclusions. Approaching recruitment of African American pedigrees with use of a multi-pronged approach that includes collaboration from the community can greatly facilitate success. While our sample has a slightly younger age of onset compared to African American cases in the general population (SEER median age for African Americans is 58 yrs), the sample approximates the US proportion of all invasive breast cancers in the US with regard to triple negative status (∼15%). Citation Format: Youjin Wang, Deborah O. Erwin, Lina Jandorf, Detric Johnson, Veronica Meadows-Ray, Mattye Willis, Heather Ochs-Balcom. Recruitment of African American breast cancer pedigrees for The Jewels in Our Genes Study: Recruitment outcomes and sample characteristics. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B12. doi:10.1158/1538-7755.DISP13-B12

Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review.

Carcinogenesis is a multistep and also a multifactorial process that involves agents like genetic and environmental factors. Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in cancer cell migration, invasion, and metastasis. Genetic variations in genes encoding the MMPs were shown in human studies to influence cancer risk and phenotypic features of a tumor. The complex role of MMPs seems to be important in the mechanism of carcinogenesis, but it is not well recognized. Rodent studies concentrated particularly on the better understanding of the biological functions of the MMPs and their impact on the pathological process, also through the modification of Mmp genes. This review presents current knowledge and the existing evidence on the importance of selected MMPs in genetic mouse models of cancer and human genetic association studies. Further, this work can be useful for scientists studying the role of the genetic impact of MMPs in carcinogenesis.

751O - Prevalence of Hoxb13G84E Germline Mutation in Uk Prostate Cancer Cases; Correlation with Tumour Characteristics and Outcomes

ABSTRACT Aim: A rare recurrent missense variant in HOXB13 rs 138213197 is associated with hereditary prostate cancer (PrCa). The frequency of this variant varies between different geographic regions. We performed a case-control study in the UK population to assess the prevalence of this variant and its implications on PrCa risk and tumour characteristics. Methods: We screened 8652 white Caucasian men from 3 UKGPCS (United Kingdom Prostate Cancer Genetic) studies and 5252 population based controls from the ProtecT study. Germline blood DNA was genotyped for G84E (rs13821397) using a custom made TaqMan assay. 2 duplicate samples and 4 positive and 4 negative controls were included on each 384 well plate.Concordance for the control samples was >99%. Results: HOXB13 rs138213197 was identified in 0.5% of healthy controls and in 1.6% of PrCa cases. The Odds Ratio (OR) was 2.93 for increased risk of developing prostate cancer and the association was stronger for cases with family history with an OR = 4.53 and young onset PrCa (diagnosed under the age of 55) with an OR = 3.1. Multivariate analysis showed no association with Gleason score, presenting PSA, TNM stage or NCCN risk score. The biochemical relapse rate was not higher for carriers. We found no evidence of interaction between this rare variant and a Polygenic Risk Score (PRS) based on common variants consisting of 71 single nucleotide polymorphisms (SNPs). As a result men with the mutation in the highest quintile of the PRS have a 5-fold higher PrCa risk compared to those in the third quintile. Conclusions: HOXB13G84E is a highly penetrant, rare genetic predisposition variant linked with young onset and familial PrCa. No assocation with an aggressive phenotype was found. The clinical application of this finding in genetic PrCa screening modelling is still unclear. Based on the estimated incidence this variant accounts for approxiately 1% of the familial PrCa risk in the UK population. Disclosure: All authors have declared no conflicts of interest.

"It takes a village": multilevel approaches to recruit African Americans and their families for genetic research.

One barrier to searching for novel mutations in African American families with breast cancer is the challenge of effectively recruiting families-affected and non-affected relatives-into genetic research studies. Using a community-based participatory research (CBPR) orientation, we incorporated several evidence-based approaches through an iterative fashion to recruit for a breast cancer genetic epidemiology study in African Americans. Our combined methods allowed us to successfully recruit 341 African American women (247 with breast cancer and 94 relatives without breast cancer) from 127 families. Twenty-nine percent of participants were recruited through National Witness Project (NWP) sites, 11% came from in-person encounters by NWP members, 34% from the Love Army of Women, 24% from previous epidemiologic studies, and 2% from a support group. In terms of demographics, our varied recruitment methods/sources yielded samples of African American women that differ in terms of several sociodemographic factors such as education, smoking, and BMI, as well as family size. To successfully recruit African American families into epidemiological research, investigators should include community members in the recruitment processes, be flexible in the adoption of multipronged, iterative methods, and provide clear communication strategies about the underlying benefit to potential participants. Our results enhance our understanding of potential benefits and challenges associated with various recruitment methods. We offer a template for the design of future studies and suggest that generalizability may be better achieved by using multipronged approaches.

BiDCG: a new method for discovering global features of DNA microarray data via an iterative re-clustering procedure.

Biclustering techniques have become very popular in cancer genetics studies, as they are tools that are expected to connect phenotypes to genotypes, i.e. to identify subgroups of cancer patients based on the fact that they share similar gene expression patterns as well as to identify subgroups of genes that are specific to these subtypes of cancer and therefore could serve as biomarkers. In this paper we propose a new approach for identifying such relationships or biclusters between patients and gene expression profiles. This method, named biDCG, rests on two key concepts. First, it uses a new clustering technique, DCG-tree [Fushing et al, PLos One, 8, e56259 (2013)] that generates ultrametric topological spaces that capture the geometries of both the patient data set and the gene data set. Second, it optimizes the definitions of bicluster membership through an iterative two-way reclustering procedure in which patients and genes are reclustered in turn, based respectively on subsets of genes and patients defined in the previous round. We have validated biDCG on simulated and real data. Based on the simulated data we have shown that biDCG compares favorably to other biclustering techniques applied to cancer genomics data. The results on the real data sets have shown that biDCG is able to retrieve relevant biological information.

On the identification of potential regulatory variants within genome wide association candidate SNP sets.

BackgroundGenome wide association studies (GWAS) are a population-scale approach to the identification of segments of the genome in which genetic variations may contribute to disease risk. Current methods focus on the discovery of single nucleotide polymorphisms (SNPs) associated with disease traits. As there are many SNPs within identified risk loci, and the majority of these are situated within non-coding regions, a key challenge is to identify and prioritize variants affecting regulatory sequences that are likely to contribute to the phenotype assessed.MethodsWe focused investigation on SNPs within lung and breast cancer GWAS loci that reached genome-wide significance for potential roles in gene regulation with a specific focus on SNPs likely to disrupt transcription factor binding sites. Within risk loci, the regulatory potential of sub-regions was classified using relevant open chromatin and epigenetic high throughput sequencing data sets from the ENCODE project in available cancer and normal cell lines. Furthermore, transcription factor affinity altering variants were predicted by comparison of position weight matrix scores between disease and reference alleles. Lastly, ChIP-seq data of transcription associated factors and topological domains were included as binding evidence and potential gene target inference.ResultsThe sets of SNPs, including both the disease-associated markers and those in high linkage disequilibrium with them, were significantly over-represented in regulatory sequences of cancer and/or normal cells; however, over-representation was generally not restricted to disease-relevant tissue specific regions. The calculated regulatory potential, allelic binding affinity scores and ChIP-seq binding evidence were the three criteria used to prioritize candidates. Fitting all three criteria, we highlighted breast cancer susceptibility SNPs and a borderline lung cancer relevant SNP located in cancer-specific enhancers overlapping multiple distinct transcription associated factor ChIP-seq binding sites.ConclusionIncorporating high throughput sequencing epigenetic and transcription factor data sets from both cancer and normal cells into cancer genetic studies reveals potential functional SNPs and informs subsequent characterization efforts.

Strategies for enrollment of African Americans into cancer genetic studies.

The enrollment of ethnically diverse populations in genetic and genomic research is vital to the parity of benefits resulting from research with biological specimens. Herein, we discuss strategies that may effectively improve the recruitment of African Americans into genetics studies. Specifically, we show that engaging physicians, genetic counselors, and community members is essential to enrolling participants into genetic studies. We demonstrate the impact of utilizing African American genetic counselors on study enrollment rates and implementing a two-page consent form that improved on a lengthy and inefficient consenting process. Lastly, we provided participants with the option of donating saliva instead of blood for study purposes. Descriptive statistics were used. Using the aforementioned strategies, recruitment goals for the Genetic Basis of Breast Cancer Subtype Study at Howard University (HU) were met. Our overall results yielded 182 participants in 18months. Recruitment strategies that involve the engagement of physicians, genetic counselors, and community members may help researchers increase the enrollment of ethnically diverse and hard-to-reach participants into genetic studies.

Naturally occurring cancers in dogs: insights for translational genetics and medicine.

Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog models are attractive, because they are genetically more similar to humans, share environmental exposures with their owners, suffer from the same diseases as humans, and receive a high level of health care. They are ideal for the study of chronic diseases, because they age five to eight times faster than humans and generally live to old age. In addition, each dog breed is on the order of 100-fold genetically simpler than the whole human or dog population. These traits make the dog ideal for the study of complex genetics of naturally occurring cancers. Here, we contrast the relative strengths of cancer genetics in humans and dogs. We propose that humans are most ideal for the study of somatic cancer genetics, whereas dogs are most ideal for germline genetics. That proposition is supported by comparison of genome-wide association studies (GWASs) in human and canine cancer. One of the advantages of dog cancer GWASs is the ability to rapidly map complex traits, conduct fine mapping and identification of causative variation, and thus be in a position to move on to functional studies. We mention how these strengths of dog models will lead to rapid advances in translational medicine.

Domestic dogs and cancer research: a breed-based genomics approach.

Domestic dogs are unique from other animal models of cancer in that they generally experience spontaneous disease. In addition, most types of cancer observed in humans are found in dogs, suggesting that canines may be an informative system for the study of cancer genetics. Domestic dogs are divided into over 175 breeds, with members of each breed sharing significant phenotypes. The breed barrier enhances the utility of the model, especially for genetic studies where small numbers of genes are hypothesized to account for the breed cancer susceptibility. These facts, combined with recent advances in high-throughput sequencing technologies allows for an unrivaled ability to use pet dog populations to find often subtle mutations that promote cancer susceptibility and progression in dogs as a whole. The meticulous record keeping associated with dog breeding makes the model still more powerful, as it facilitates both association analysis and family-based linkage studies. Key to the success of these studies is their cooperative nature, with owners, scientists, veterinarians and breed clubs working together to avoid the cost and unpopularity of developing captive populations. In this article we explore these principals and advocate for colony-free, genetic studies that will enhance our ability to diagnose and treat cancer in dogs and humans alike.

Semiparametric odds rate model for modeling short-term and long-term effects with application to a breast cancer genetic study.

The proportional odds model is commonly used in the analysis of failure time data. The assumption of constant odds ratios over time in the proportional odds model, however, can be violated in some applications. Motivated by a genetic study with breast cancer patients, we propose a novel semiparametric odds rate model for the analysis of right-censored survival data. The proposed model incorporates the short-term and long-term covariate effects on the failure time data and includes the proportional odds model as a nested model. We develop efficient likelihood-based inference procedures and establish the large sample properties of the proposed nonparametric maximum likelihood estimators. Simulation studies demonstrate that the proposed methods perform well in practical settings. An application to the motivating example is provided.

Homogeneity in Case/Control Numbers and North Indian Caste Criteria in Cervical Cancer/Female Urology Genetic-Studies at a Premier Medical Research Institute in Lucknow, India

Cervical cancer has emerged as a major public health problem in Lucknow and New York in the 21st century. Cancer genetic studies are essential to identify/stratify disease-susceptible individuals in a population-based cohort. Sample size homogeneity and North Indian caste in female urology genetic-studies are significant issues in meaningful interpretation of data. A review of scientific literature using Pubmed database was conducted, including an assessment of cervical cancer genetic studies conducted as part of the author's doctoral dissertation at a premier Lucknow-based medical research Institute. Sample size numbers and caste criteria in the North Indian cohort (N≤400 subjects) were evaluated with homogeneity in the sample cohort data set(s). Subgroup caste-stratification of North Indian cohort is equally essential, for instance, Brahmin (e.g. Pandey), Vaishya (e.g. Mittal), Rajput (e.g. Singh) and Kshudra (e.g. Yadav) during the conception and design of genetics-based studies. Sample size homogeneity in histopathologically confirmed case and control numbers and caste-based stratification in a North Indian cohort is essential in single nucleotide polymorphism (SNP) studies in cervical cancer susceptible populations to draw more definitive conclusions.