All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.

Cell-cycle checkpoints and cancer

Purpose Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis. Methods We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach. Results Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-...

/pdf/meta-analysis-of-brca1-and-brca2-penetrance-52898vbzms.pdf

Meta-analysis of BRCA1 and BRCA2 penetrance

Gene-environment interaction research in psychiatry is new, and is a natural ally of neuroscience. Mental disorders have known environmental causes, but there is heterogeneity in the response to each causal factor, which gene-environment findings attribute to genetic differences at the DNA sequence level. Such findings come from epidemiology, an ideal branch of science for showing that a gene-environment interactions exist in nature and affect a significant fraction of disease cases. The complementary discipline of epidemiology, experimental neuroscience, fuels gene-environment hypotheses and investigates underlying neural mechanisms. This article discusses opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene-environment interactions.

Gene–environment interactions in psychiatry: joining forces with neuroscience

Context Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Main Outcomes Measures Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Conclusions Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.

https://jamanetwork.com/journals/jama/articlepdf/186510/joc05109_967_975.pdf

Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality

BackgroundInherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. MethodsWe recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. ResultsA total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1603144

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.

https://science.sciencemag.org/content/sci/302/5645/643.full.pdf

Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.

In a time of emerging genetic tests and technologies, genetic counselors are faced with the challenge of translating complex genomic data into information that will aid their client's ability to learn about, understand, make, and cope with decisions relating to genetic diagnoses. The first of two companion articles in this issue examines the role of the genetic counselor, particularly in counseling individuals at risk for or diagnosed with breast cancer, in an era of high-tech health care and gene patents.

/pdf/genetic-counselors-translating-genomic-science-into-clinical-50pcepvvov.pdf

Genetic counselors: translating genomic science into clinical practice

Genetic counseling is an expanding field in the era of genomic medicine. This unique medical specialty provides clinical health care, education, and emotional support to individuals and families facing genetic and inherited diseases. Genetic counselors provide services to patients across the lifespan by assessing family and environmental history to determine disease risk; assisting in genetic testing, diagnosis, and disease prevention and management; and offering psychosocial and ethical guidance to help patients make informed, autonomous health care and reproductive decisions (Figure ​(Figure1).1). The purpose of this article is to provide an authoritative review of genetic counseling, its role in the front lines of genetic health, and its impact on medical research, education, and patient care.



Figure 1

Genetic counseling is a unique medical specialty that provides clinical health care for patients across the lifespan facing genetic and inherited diseases.

/pdf/genetic-counseling-throughout-the-life-cycle-1gl0pevwut.pdf

Genetic counseling throughout the life cycle

Joan H. MarksView Large Image | View Hi-Res Image | Download PowerPoint SlideI was deeply honored to receive the ASHG 2003 Award for Excellence in Medical Genetics Education. I am grateful to the committee and those who nominated me for this wonderful honor. This award means not only a great deal to me personally but also to all members of the new profession of genetic counseling.It is a tradition to thank one’s colleagues for their participation in a research project. In this instance, I believe that the success of master’s-level genetic counselors, a program that was initiated at Sarah Lawrence College, is due to a major extent to those “pioneer” graduates from Sarah Lawrence. These early graduates established the field by showing what they could accomplish in the practice of medical genetics as advocates for patients seeking understanding of their particular genetic risks. Several of the early graduates were hired by the geneticists with whom they did their student training. These centers, all in the New York area, included Albert Einstein College of Medicine, New York Hospital–Cornell College of Medicine, Creedmoor Psychiatric Hospital, Long Island Jewish Hospital, and, in the late 70s, Presbyterian Hospital–College of Physicians and Surgeons, Columbia University. By 1980, the Human Genetics Program at Sarah Lawrence was attracting students from all over the country, and these graduates were also recruited to join a genetic counseling service in many states across the nation.When the first grants were awarded to states under the National Genetics Diseases Act of 1976, most of the states who applied for funds to develop a statewide genetic service program included salaries to recruit master's-level genetic counselors. The fact that an innovative, high-risk program in graduate education could be initiated and flourish at Sarah Lawrence—with a concentration in the humanities, not the sciences—owes a lot to the culture of the college, a culture that emphasizes initiative and the individual.The hallmark of the training of genetic counselors is based on the premise that understanding that the emotional component of genetic risk is central to providing good genetic services. That integration of medical-genetics training with psychological-counseling skills has remained at the core of all graduate programs training genetic counselors now offered in the United States and abroad.The curriculum at Sarah Lawrence originally concentrated on basic science courses, such as human physiology, medical genetics, probability and statistics, and cytogenetics. By the mid-70s, course work was developed in the psychological component of illness and loss. At the same time, a serious effort was made to recruit students who had previous experience working with patients who had undergone traumatic, stressful situations. As our contact with patients seeking genetic services increased, so did our appreciation that the emotional component of being at risk for passing on one’s malfunctioning genes was a traumatic experience for most patients. Learning to provide supportive care and sensitivity tailored to each patient’s particular dynamic was something that needed to be taught. Selecting a student who had already shown an interest in providing this level of care seemed promising for future training. All applicants were required to have a personal interview with the director and assistant director of the training program.The counseling component of the curriculum soon matched the number of hours devoted to the sciences. A two-semester seminar in genetic counseling was developed by a psychiatrist. I began to work individually with students in a weekly seminar, as well as one-on-one conferences, both devoted to helping students open up to their own life experiences and, as patient contacts developed, to their patients' emotional needs and problems in seeking genetic services. A one-semester course on interviewing, based on the concepts of Carl Rogers, was introduced in the early 1980s and remains part of the core curriculum today. The science curriculum expanded to include reproductive genetics, developmental biology, biochemistry, introduction to clinical medicine, and a thesis requirement. An oral exam based on developing an impromptu case plan for a typical genetics referral was also introduced.Going back to the 1970s, the emphasis was on prenatal diagnosis and birth defects. Over the decades, as our understanding of the role of genetic risk for diseases has expanded, so has the role of the genetic counselor. In the next decades, genetic counseling will undoubtedly have an increasing and ever-more-challenging role in delivering health services. Alan Guttmacher has said, “Stunning scientific and technological advances in genetics will mean little if they do not benefit people.” That is the challenge today for genetic counselors as they begin to apply the scientific knowledge that the Human Genome Project has made available. The process of genetic counseling also includes, to a large extent, the need to educate patients and the public in a nontechnological language that will be understandable to people at all intellectual levels. These same skills must—and will—be utilized to play an important role in helping the public become aware of the many facets of our new knowledge and its implications for individual patients wanting to know about their genetic makeup.I was first invited to speak before the American Society of Human Genetics when I had submitted an abstract about the Sarah Lawrence Human Genetics Program for the 1974 meeting in Portland, Oregon. On a hot July day, Fred Hecht, the program chair, called me to say my paper had been chosen for the plenary session! I was shocked! I assured him I had no intention of presenting this paper, but that I merely wanted to put the new profession on the map! He responded that I had no choice but to present the talk! That was a unique day for me, as I had never presented a talk to a large group, not even the PTA! As Victor McKusick introduced me to the audience, he referred to me as “Doctor Marks!” I had a few moments on the way to the podium to decide whether to accept my promotion to medical doctor or to concentrate on the job for the day: to convince a doubtful audience that master’s-level-trained genetic counselors had a real contribution to make in the world of medical genetics and health care.In the year 2003, there has been a remarkable acceptance of the importance of the role of the master’s-level-trained genetic counselor. Traditionally, based in genetics clinics and medical centers, that role now encompasses all medical specialties, health-care management, health-professional education, public health, and the use of technology to deliver genetic services. In cancer genetics alone, the genetic counselor has become an integral member of the oncology team. Industry, too, continues to recruit many genetic counselors to both promote utilization of genetic screening tools, but also to educate management about medical genetics on a worldwide basis.Today, I am still not an M.D.! But this award signifies that medical genetics has accepted the profoundly important work that genetic counselors perform as members of the genetics team. While I am enormously grateful for the recognition of my role in this development, I am even more appreciative of the fact that the committee’s decision commends the field of genetic counseling itself for our role in helping so many patients at genetic risk for illness and disability and for improving the quality of care these patients receive.

2003 ASHG Award for Excellence in Human Genetics Education. The importance of genetic counseling.

In the fifty years from 1956 to 2006 the field of human genetics will have moved from the numbering of the 46 human chromosomes to the expected mapping of the approximately 35,000 human genes This explosion of knowledge about genetic aspects of human health has been coupled with similar strides in reproductive technologies to overcome infertility or other barriers to the birth of healthy children The need for the medical community to communicate this information in a useful way to those who may benefit from it has led to the growth of the profession of genetic counseling

Joan H. Marks

Papers

Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.

Genetic counselors: translating genomic science into clinical practice

Genetic counseling throughout the life cycle

2003 ASHG Award for Excellence in Human Genetics Education. The importance of genetic counseling.

Reproductive Health Technology and Genetic Counseling