Field Of Cancer Genetics Research Articles

The Evolution of Genetic Testing from Focused Testing to Panel Testing and from Patient Focused to Population Testing: Are We There Yet?

The field of cancer genetics has evolved significantly over the past 30 years. Genetic testing has become less expensive and more comprehensive which has changed practice patterns. It is no longer necessary to restrict testing to those with the highest likelihood of testing positive. In addition, we have learned that the criteria developed to determine who has the highest likelihood of testing positive are neither sensitive nor specific. As a result, the field is moving from testing only the highest risk patients identified based on testing criteria to testing all cancer patients. This requires new service delivery models where testing can be mainstreamed into oncology clinics and posttest genetic counseling can be provided to individuals who test positive and those with concerning personal or family histories who test negative. The use of videos, testing kiosks, chatbots, and genetic counseling assistants have been employed to help facilitate testing at a larger scale and have good patient uptake and satisfaction. While testing is important for cancer patients as it may impact their treatment, future cancer risks, and family member's cancer risks, it is unfortunate that their cancer could not be prevented in the first place. Population testing for all adults would be a strategy to identify individuals with adult-onset diseases before they develop cancer in an attempt to prevent it entirely. A few research studies (Healthy Nevada and MyCode) have offered population testing for the three Centers for Disease Control and Prevention Tier 1 conditions: hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia finding a prevalence of 1 in 70 individuals in the general population. We anticipate that testing for all cancer patients and the general population will continue to increase over the next 20 years and the genetics community needs to help lead the way to ensure this happens in a responsible manner.

Abstract 2099: EM-seq enables accurate and precise methylome analysis of challenging DNA samples

Abstract DNA isolated from blood draws (cell-free DNA (cfDNA)) or from archival material like formalin fixed paraffin embedded (FFPE) tissues have advanced the field of cancer genetics. DNA methylation (5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC)) is a key epigenetic factor that plays an important role in cellular processes and it's misregulation results in diseased states like cancer. Advances in the field of sample preparation from biological matrices and genomics have enabled cancer biomarker identification based on methylation profiling. Bisulfite sequencing has been the gold standard for detection of methylation and is employed for both targeted and whole genome methylation analysis. However, the chemical based bisulfite conversion of cytosines to uracils leads to DNA damage which subsequently translates to shorter DNA insert sizes as well as biases in the data. DNA obtained from cfDNA and FFPE samples is typically of low quality and quantity making DNA methylation profiling using the harsh bisulfite conversion challenging. Robust biomarker detection relies primarily on the ability to profile methylation accurately. To overcome the drawbacks of bisulfite sequencing, we developed an enzyme based methylation detection technology, called NEBNext® Enzymatic Methyl-Seq (EM-Seq™), that minimizes damage to DNA enabling longer insert sizes, lower duplication rates and minimal GC bias resulting in more accurate quantification of methylation in the sample DNA. Using EM-Seq, we profiled cfDNA and lung FFPE DNA. Results for these challenging DNA types showed that the EM-Seq libraries had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to WGBS libraries. EM-seq libraries also identified a higher number of CpG's with even coverage facilitating accurate methylation calling. In conclusion, EM-Seq libraries have superior sequencing metrics resulting in robust methylation profiling for these types of challenging DNA samples. Citation Format: V K Chaithanya Ponnaluri, Louise Williams, Matthew A. Campbell, Vaishnavi Panchapakesa, Romualdas Vaisvila, Bradley Langhorst, Eileen Dimalanta, Theodore B. Davis. EM-seq enables accurate and precise methylome analysis of challenging DNA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2099.

CRISPR Cas System: An efficient tool for cancer modelling.

The Clustered Regularly Interspaced Short Palindromic Repeats-Cas-9 (CRISPR-Cas9) system has been a revolutionising tool in the field of molecular genetics, which provides a versatile range of editing potentials. Researchers can produce breaks or alter genomes with ease using the system. Cancer is one of the multi-gene diseases whose genes need to be studied in detail. The CRISPR-Cas9 technology may also provide a promising potential in the field of cancer genetics. The current narrative review comprised 50 research articles which were keenly analysed and the applications and outcomes of CRISPR-Cas9 system in cancer genetics were comprehensively and critically discussed. It was concluded that application of the system had great potential to help understand cancer biology of various types and could be used for its genetic modelling. However, much work is still needed to be done to apply the technology for understanding the mechanism of cancers and to help in the designing of appropriate therapies.

The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene.

The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.

Abstract 820: Enzymatic Methyl-Seq: methylome analysis of challenging DNA samples

Abstract DNA isolated from blood draws (cell-free DNA (cfDNA)) or from archival material like formalin fixed paraffin embedded (FFPE) tissues have advanced the field of cancer genetics. DNA methylation (5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC)) is a key epigenetic factor that plays an important role in cellular processes and it’s misregulation results in diseased states like cancer. Advances in the field of sample preparation from biological matrices and genomics have enabled cancer biomarker identification based on methylation profiling. Bisulfite sequencing is the standard method to detect methylation and has been employed for both targeted and whole genome methylation analysis. However, the chemical based bisulfite conversion of cytosines to uracils also results in DNA damage which subsequently results in shorter DNA insert sizes as well as introducing bias into the data. Robust biomarker detection relies primarily on the ability to profile methylation accurately. Analysis of DNA methylation from cfDNA and FFPE DNA is challenging as the DNA is typically of low quality and quantity. To overcome the drawbacks of bisulfite sequencing, we developed an enzyme based methylation detection technology, called NEBNext Enzymatic Methyl-Seq (EM-Seq). DNA damage is minimized enabling longer insert sizes, lower duplication rates and minimal GC bias resulting in more accurate quantification of methylation in the sample DNA. Using EM-Seq, we profiled cfDNA and FFPE DNA from multiple tissue types. Results for these challenging DNA types showed that the EM-Seq libraries had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to WGBS libraries. These libraries also identified a higher number of CpG’s and the estimated global methylation levels were in good agreement with the absolute levels quantified using LC/MS. In conclusion, EM-Seq libraries have superior sequencing metrics resulting in robust methylation profiling for these types of challenging DNA samples. Citation Format: Louise Williams, V K Chaithanya Ponnaluri, Brittany S. Sexton, Lana Saleh, Katherine Marks, Mala Samaranayake, Laurence Ettwiller, Shengxi Guan, Heidi E. Church, Nan Dai, Esta Tamanaha, Erbay Yigit, Bradley Langhorst, Zhiyi Sun, Thomas C. Evans, Romualdas Vaisvila, Eileen Dimalanta, Theodore B. Davis. Enzymatic Methyl-Seq: methylome analysis of challenging DNA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 820.

Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy

The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.

Profile of Scott W. Lowe

As a graduate student at the Massachusetts Institute of Technology, Scott Lowe became interested in cancer genetics. The phenomenon that drew his interest was called oncogene cooperation—the idea that it takes multiple oncogenes working together to turn a normal cell into a tumor cell. “That was an exciting concept because it could explain why the development of cancer in patients probably involved more than one mutation, and you could find certain combinations of oncogenes that, when introduced into normal cells, would collaborate to make the cell fully malignant,” says Lowe, now a professor at Memorial Sloan Kettering Cancer Center. “We became interested in the biological and mechanistic basis for why certain combinations of oncogenes interact,” he says. Scott W. Lowe. Image courtesy of Lynn Boss (Memorial Sloan Kettering Cancer Center, New York). Those early questions would lead Lowe toward many landmark discoveries concerning how oncogenes interact to drive tumorigenesis and how the genotype of a cancer cell can dictate its response to cancer therapy. Over the ensuing years, he combined mouse models, genetic tools, and cancer genomics in innovative ways to elucidate how cancer mutations lead to tumor formation. Lowe describes some of his latest advances in his Inaugural Article (1). For his many discoveries in the field of cancer genetics, Lowe was elected to the National Academy of Sciences in 2017. When Lowe started studying oncogenes, he encountered a seemingly counterintuitive result. Although the oncogenes made cells grow in an uncontrolled manner, they also caused them to die. Lowe hypothesized that the cells might have inbuilt mechanisms that can sense problems and eliminate themselves through the process of apoptosis. “Through the course of investigating that hypothesis, we stumbled across p53, which was a gene that is known to inhibit cancer,” he says. Lowe noticed that certain oncogenes could increase …

Integrating surgery and genetic testing for the modern surgeon.

The field of cancer genetics is rapidly evolving and several genetic mutations have been identified in hereditary cancer syndromes. These mutations can be diagnosed via routine genetic testing allowing prompt intervention. This is especially true for certain variants of colorectal, breast, and thyroid cancers where genetic testing may guide surgical therapy. Ultimately, surgical intervention may drastically diminish disease manifestation or progression in individuals deemed as high-risk based on their genetic makeup. Understanding the concepts of gene-based testing and integrating into current surgical practice is crucial. This review addresses common genetic syndromes, tests, and interventions salient to the current surgeon.

Association between rs11614913, rs3746444, rs2910164 and occurrence of breast cancer in Iranian population

BackgroundBreast cancer is a complex and heterogeneous disease that has several subgroups with different clinical outcomes. This disease is the second leading cause of cancer after lung cancer. The incidence of this cancer is high among women, and it is one of the major causes of death among them. Determining the susceptibility of the patient to the disease and consequently using appropriate methods for early detection of the disease play a significant role in prognosis and survival rate of the patient. Therefore, studies which identify markers of susceptibility to the disease and consequently the use of early detection strategies are considered as one of the attractive areas of research in the field of cancer genetics. ObjectivesIn this study the association of rs11614913, rs3746444 and rs2910164 polymorphisms with breast cancer was examined in hsa-mir-196a2 and hsa-mir-499 and hsa-mir146a genes respectively. MethodsThe present case–control study was included 100 patients with breast cancer and 150 healthy controls. After DNA extraction, genotypic distribution of SNPs rs11614913, rs3746444 and rs2910164 was examined in hsa-mir-196a2, hsa-mir-499 and hsa-mir146a genes respectively via ARMS-PCR for both groups. The frequency of various alleles of each polymorphism was examined in both control and study groups using Pearson chi-square test. The P values less than 5% were considered as significant differences between the two groups. Finally, the odds ratio of each allele and genotype was studied. ResultsAfter comparing the frequency of polymorphisms in two groups, a significant association was found between the occurrence of breast cancer in Iranian population and rs3746444 (P-value<0.05). Other polymorphisms were not significantly associated with the incidence of breast cancer (P-value>0.05). The results indicated an increased risk of breast cancer in patients with C allele compared to patients without this allele. ConclusionAccording to our results rs3746444 has a significant association with occurrence of breast cancer in Iranian population.

Integrating next-generation sequencing into clinical oncology: strategies, promises and pitfalls

We live in an era of genomic medicine. The past five years brought about many significant achievements in the field of cancer genetics, driven by rapidly evolving technologies and plummeting costs of next-generation sequencing (NGS). The official completion of the Cancer Genome Project in 2014 led many to envision the clinical implementation of cancer genomic data as the next logical step in cancer therapy. Stemming from this vision, the term ‘precision oncology’ was coined to illustrate the novelty of this individualised approach. The basic assumption of precision oncology is that molecular markers detected by NGS will predict response to targeted therapies independently from tumour histology. However, along with a ubiquitous availability of NGS, the complexity and heterogeneity at the individual patient level had to be acknowledged. Not only does the latter present challenges to clinical decision-making based on sequencing data, it is also an obstacle to the rational design of clinical trials. Novel tissue-agnostic trial designs were quickly developed to overcome these challenges. Results from some of these trials have recently demonstrated the feasibility and efficacy of this approach. On the other hand, there is an increasing amount of whole-exome and whole-genome NGS data which allows us to assess ever smaller differences between individual patients with cancer. In this review, we highlight different tumour sequencing strategies currently used for precision oncology, describe their individual strengths and weaknesses, and emphasise their feasibility in different clinical settings. Further, we evaluate the possibility of NGS implementation in current and future clinical trials, and point to the significance of NGS for translational research.

A role for epigenetics in the formation of chromosome translocations in acute leukemia

In general, the field of cancer genetics seems to have shifted its focus from cancer-associated genes to cancer-associated epigenetic activity. An abundance of evidence suggests that epigenetic malfunction, such as aberrant histone modification, and altered DNA methylation, is at the root of much, if not most aberrant gene expression associated with cancer. However, a role for epigenetics in physical DNA changes, such as chromosome rearrangements, is less obvious, and certainly less well understood. A growing body of evidence suggests that epigenetics may play a role in many of the steps of aberrant chromosome recombination, especially chromosome translocations, associated with cancers such as acute leukemias.

Risk Assessment, Genetic Counseling, and Clinical Care for Hereditary Breast Cancer

During the last 30 years, key advances in the field of cancer genetics have improved identification of high-risk families in which cancer risk can be linked to mutations in cancer susceptible genes. Identification of individuals with heritable cancer risk may influence short- and long-term medical management issues. Heightened screening and risk reducing options can offer lifesaving interventions for the woman and family members who are at risk.

Ancestry, Temporality, and Potentiality: Engaging Cancer Genetics in Southern Brazil.

In this paper I examine the variety of ways potential is articulated, entailed, and produced in how the field of cancer genetics is being constituted as a domain of transnational research and an emerging site of health-care intervention in southern Brazil. Drawing on analysis of fieldwork in Brazilian cancer-genetics clinics, I explore how different expressions of potential come to inform dynamically the pursuit of prevention, care, and research as diversely scaled investments for those working and living with cancer-genetics knowledge and technologies. It illustrates how specific temporalities help to constitute and "abductively" frame the meaning of these different potentials particularly as this relates to a focus on ancestry. Colonial histories of migration, the embodied effects of dietary habits, or the moral failings of near and distant ancestors as well as promissory futures and the contingency of lived lives become at different times templates for identifying, materializing, and transforming how the potential of cancer genetics in Brazil is articulated. Potential is also expressed through an idiom of "choice" in different efforts to situate participation in cancer-genetics research as prevention or to negotiate access to basic public health. I explore how these expressions of cancer genetics as potential powerfully yet unevenly work to sustain knowledge practices as well as propel patients and their families into fledgling domains of clinical practice and scientific research. At the same time there is always an "excess of meaning" in these endeavors that make visible lines of fracture and disjuncture in collective efforts to make future histories of and from the pursuit of cancer genetics in southern Brazil.

A guide to cancer genetics in clinical practice

The field of cancer genetics has rapidly emerged from the early nineties after the identification of the RB1 gene, the germline monoallelic mutations of which are associated with a 90% risk of retinoblastoma. The identification of genes associated with a high risk of frequent cancers, such as breast and colorectal cancers, has rapidly led to the development of cancer genetic clinics. Although less than 5% of cancers are linked to highly predisposing gene mutations, because of the high incidence of cancers one individual among 200 is affected by cancer genetics. Thus, cancer genetics is one of the emblematic fields of personalized genomic medicine and is prone to take part in the renewed practices of genetic medicine. However, this new field, and especially the management of high-risks individuals, still needs to be translated to the clinic. Sue Clark, a consultant colorectal surgeon in charge of the polyposis registry of the UK, has edited a guide to cancer genetics published by Tfm publishing. She was joined by a number of specialists of each of the reviewed syndromes. The guide starts with two chapters introducing to the general principles of Mendelian diseases and molecular genetics, and to cancer inheritance. A third chapter is dedicated to the ethical and legal aspects of genetic testing in the field of cancer genetics. The most frequent inherited cancer syndromes are reviewed in the next 10 chapters, according to the same plan: genetics, clinical picture, diagnosis, management, and future. A last chapter is an interesting reflexion on cancer genetics centers, and the future of cancer genetics practice including the introduction of the growing body of knowledge on multifactorial cancer inheritance. Despite some data to update, such as the CHK2 gene that is not any more involved in the Li-Fraumeni syndrome, this guide is an easy and pleasant read thanks to many tables, illustrations, and key points at the end of each chapter. This guide to cancer genetics is meant for students, genetic counsellors, geneticists not specialized in cancer genetics, and clinicians managing at risk individuals searching for an introduction to the cancer genetics field. If these were Sue Clark's objectives, they have been fully accomplished▪

Insights from next generation sequencing of the cancer genome

This detailed review provides a history and update of the complex field of cancer genetics. Using examples of progress such as the development of imatinib for chronic myeloid leukemia (which stemmed from the recognition of the Philadelphia chromosome in the 1960s), Michael Stratton, Director of the Sanger Institute in Cambridge is confident that we are now entering the end game of cancer genome sequencing. This has led to other drug therapies, based on knowledge of the molecular changes in some cancers, lung and breast cancers for example.

In Memoriam: Dr. Charles Epstein (1993–2011)

In Memoriam: Dr. Charles Epstein (1993–2011)

Tumor hypoxia and genetic alterations in sporadic cancers

The cancer genome contains many gene alterations. How cancer cells acquire these alterations is a matter for discussion. One hypothesis is that cancer cells obtain mutations in genome stability genes at an early stage of tumor development, which results in genetic instability and generates a gene pool that enhances cellular proliferation and survival. Another hypothesis puts its emphasis on the natural selection of gene mutations for fitness. Recent data for systematic cancer genome sequencing shows that mutations in stability genes are rare in human sporadic cancers. Instead, many “passenger” mutations that do not drive the carcinogenesis process have been found in the cancer genome. Both the hypotheses mentioned above fall short in explaining recent data. Recently, many studies demonstrate the role of the tumor microenvironment, especially hypoxia and reoxygenation, in genetic instability. In this review, literature will be presented which supports a third hypothesis, i.e. that hypoxia/re-oxygenation induces genetic instability.

The growing role for genetic counseling in endocrinology

The field of cancer genetics and genetic testing is expanding rapidly. As our understanding of the hereditary nature of endocrine tumors increases, the role of genetic counseling on the multidisciplinary endocrinology team is becoming more critical. This brief review will highlight the role of the certified genetic counselor in this setting. Genetic counseling and testing may aid in the management of the endocrine patient through early diagnosis and detection of disease, by optimizing surgical decision-making and improving overall survival. Certified genetic counselors assist the endocrinology team by eliciting a detailed pedigree, determining the appropriate genetic test to order, obtaining informed consent, interpreting complex genetic test results, providing psychosocial and family counseling, and assessing which family members are at risk. Many endocrine tumors can be caused by a variety of different genes and investment in the genetic counseling process likely increases the chance that the correct genetic test is ordered, results are interpreted accurately, and adequate informed consent and counseling is offered. The field of endocrine genetics is growing exponentially and testing will likely play an even greater role in surveillance, medical management, and surgical decision-making in the next decade. Genetic counseling both pretesting and posttesting is essential to accurate, cost-efficient care for the endocrine patient and the entire family.

A Collaborative Approach to Genetic Testing: A Community Hospital's Experience

The field of cancer genetics is evolving rapidly, and much has changed over the past ten years in the way services are being provided and by whom they are being provided. We recount here our experience with the evolution of cancer genetic services in a community setting, focusing on collaboration with non-genetics providers to offer genetic testing for hereditary cancer. This approach allows for the most effective use of genetic counselors' expertise for challenging cases, and enables the patient to remain within their community to allow for better access to resources for long-term follow-up.

Molecular genetics of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are relatively rare neoplasias arising from the embryonic neural crest, neuroectoderm and endoderm. GEP NETs occur either sporadically or as part of endocrine tumor susceptibility syndromes such as multiple endocrine neoplasia type 1 (MEN1), von Hippel Lindau (VHL) syndrome, neurofibromatosis (NF-1), and possibly tuberous sclerosis (TSC). The overall incidence of GEP NETs shows a significant increase over the past three decades. Improved understanding of the molecular genetics associated with these lesions will likely enhance the diagnosis and treatment of patients with GEP NET. The molecular and clinical genetics of familial GEP NETs have been further elucidated by the characterization of the tumor suppressor genes, MEN1, VHL, NF-1, TSC1, and TSC2. The vastly improved technology in the field of cancer genetics with higher resolution of the study of genetic alterations, and the ability of unbiased mutational analyses of entire tumor genomes is likely to further the understanding of the genetic mechanisms of sporadic GEP NET as well. Recent advances in the molecular genetics of sporadic and familial GEP NET are reviewed.