Committee opinion no. 634: Hereditary cancer syndromes and risk assessment.

A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited mutations in one or more genes. Cases of cancer commonly encountered by obstetrician-gynecologists or other obstetric-gynecologic providers--such as breast cancer, ovarian cancer, and endometrial cancer--are features of specific hereditary cancer syndromes. The most common hereditary cancer syndromes related to gynecologic cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and Peutz-Jeghers syndrome. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Screening should include, at minimum, a personal cancer history and a first- and second-degree relative cancer history that includes a description of the type of primary cancer, the age of onset, and the lineage (paternal versus maternal) of the family member. In addition, a patient's ethnic background can influence her genetic risk. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing.

Hereditary gynecologic cancers: risk assessment, counseling, testing and management.

Gynecologists and gynecologic oncologists have a major role in identifying patients at increased risk of inherited cancer syndromes. Awareness of the biological and familial risk factors is useful in this practice, and can assist patients and families in navigating the follow-up for these complex disorders. Large national and international cohorts of women with known BRCA1/2 mutations or high risk continue to collect data in an attempt to better understand genetic risk, risk modifiers, and quality-of-life impact or screening, testing and risk reduction strategies. The Consortium of Investigators of Modifiers of BRCA1/2 is beginning to identify other genetic modifiers of BRCA1/2 risk and cancer cluster regions in an attempt to better individualize site specific cancer risk and prevention strategies. The Gynecologic Oncology Group has initiated along-term follow-up study to the Gynecologic Oncology Group 199 protocol, which will continue to advance understanding of patient decisions, quality-of-life impact, and other genetic factors responsible for cancer initiation and progression. These and other large consortia are invaluable resources with massive datasets requiring herculean analyses that will continue to rapidly advance our present knowledge and management of women with hereditary cancer syndromes.

[Genetic predisposition to breast and ovarian cancer: importance of test results]. / Prédisposition génétique aux cancers du sein et de l'ovaire: importance des résultats des tests.

Oncogenetic consultations and predictive BRCA1/2 testing are intertwined processes and the specific impact of these genetic tests if performed alone through direct-to-consumer offers remains unknown. Noteworthy, the expectations of patients vary with their own status, whether they are affected or not by breast cancer at the time genetic testing is performed. The prescription of genetic tests for BCRA mutations has doubled in France between 2003 and 2009. There is a consensus on the fact that genetic results disclosure led to a significant increase in the knowledge and understanding that the patients have of the genetic risk and also changed the medical follow-up of these patients. Evaluating the psychological burden of tests disclosure did not reveal any major distress in patients who are followed by high-quality multidisciplinary teams. Longitudinal cohorts studies have now evaluated the perception and behaviour of these patients, and observed sociodemographic as well as geographic and psychosocial differences both in the acceptation of prophylactic strategies such as surgery, and time to surgery.

Working toward an understanding of the impact of hereditary cancers.

Hereditary diffuse gastric cancer is a genetically inherited aggressive form of stomach cancer. Once the person is diagnosed as having this gene, they have a 75%-80% chance of inheriting the cancer. People who are at risk of this genetic mutation have to meet many challenges relating to the implications of the disease. An understanding is required by nurses to guide them in the provision of care for those afflicted with this inherited form of gastric cancer. A review of literature has been undertaken relating to other genetically inherited cancers including hereditary nonpolyposis colon cancer, familial adenomatous polyposis, and hereditary lobular breast cancer. The findings from the literature assist nurses in understanding the physical and psychological implications of genetically inherited cancer; however, further study is required to gain a complete understanding of the implications of hereditary diffuse gastric cancer.

Familial pancreatic cancer in Italy. Risk assessment, screening programs and clinical approach: a position paper from the Italian Registry.

In Italy, pancreatic cancer is the fifth leading cause of tumor related death with about 7000 new cases per year and a mortality rate of 95%. In a recent prospective epidemiological study on the Italian population, a family history was found in about 10% of patients suffering from a ductal adenocarcinoma of the pancreas (PDAC). A position paper from the Italian Registry for Familial Pancreatic Cancer was made to manage these high-risk individuals. Even though in the majority of high-risk individuals a genetic test to identify familial predisposition is not available, a screening protocol seems to be reasonable for subjects who have a >10-fold greater risk for the development of PDAC. However this kind of screening should be included in clinical trials, performed in centers with high expertise in pancreatic disease, using the least aggressive diagnostic modalities.

Recognition and management of hereditary colorectal cancer syndromes.

Over 1,900 colorectal tumors will arise in association with a hereditary colorectal cancer syndrome in Spain in 2009. The genetic defects responsible for the most common syndromes have been discovered in recent years. Genetic testing helps diagnose affected individuals and allows identification of individuals at-risk. Colonoscopy and prophylactic colectomy decrease colorectal cancer incidence and overall mortality in patients with hereditary colon cancer. Extracolonic tumors are frequent in these syndromes, so specific surveillance strategies should be offered.

Screening for colon cancer.

Colorectal cancer screening reduces mortality in individuals 50 years and older. Each of the screening tests currently available has advantages and limitations, and there is no consensus as to which test or combination of tests is best. What is clear, however, is that the rates of colorectal cancer screening remain low. This review summarizes the clinical evidence supporting colorectal cancer screening in the average risk population and in high risk groups, discusses the advantages and disadvantages of the available screening tests, outlines the currently recommended guidelines for screening based on risk category, and discusses new and emerging technologies for colorectal cancer screening.

Cancer screening in older adults in an era of genomics and longevity.

OBJECTIVES: To provide an overview of cancer genomics and cancer screening in older adults with a focus on breast, prostate, and colon cancers. DATA SOURCES: Journal articles, research articles, and web sites. CONCLUSION: Cancer screening in older populations is often in the context of one or more co-morbid conditions, cancer survivorship, genomic information, and competing health priorities. The field of cancer screening has outgrown the tools available to enable health care providers and older adults to make informed cancer screening decisions. Research is needed to develop clinical screening tools that integrate age, cancer risk, life expectancy, and comorbidity. IMPLICATIONS FOR NURSING PRACTICE: Health care providers are faced with opportunities and challenges in the prevention and early detection of cancer in older Americans.

Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases.

BACKGROUND: To identify associations of other cancers with hereditary prostate cancer (HPC) we estimated relative risks (RRs) of 36 different cancers in relatives of prostate cancer cases in the Utah Population Data Base (UPDB), which combines genealogical and cancer data for Utah. METHODS: We utilized known genetic relationships between prostate cancer cases and their relatives with cancer, combined with age- and sex-specific cancer rates calculated internally from the UPDB, to estimate RRs for cancer in relatives of prostate cancer cases. RESULTS: Multiple other cancers were observed in excess in both first- and second-degree relatives of HPC cases including colon cancer, non-Hodgkins lymphoma, multiple myeloma, rectal cancer, cancer of the gallbladder, and melanoma (skin). CONCLUSIONS: This analysis supports the existence of heritable prostate cancer syndromes that include other cancers. We hypothesize that the study of homogeneous pedigrees co-segregating prostate cancer and another cancer could allow more straightforward localization and identification of the gene(s) responsible.

Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset.

Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate-specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes.

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing.

Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2- from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics.

Ethical implications of genetic testing for breast cancer susceptibility.

The identification of gene mutations involved in hereditary breast cancer is a major recent scientific discovery, enabling us to identify women at very high risk, and also providing the means to understand the biology of breast cancer and to explore novel preventive strategies. Yet, it carries medical, psychological, ethical and social implications. This paper is a review of all the ethical implications of genetic testing for breast cancer predisposition, as well as an attempt to discuss the more philosophical questions of women facing BRCA testing. To what extent does the individual benefit from genetic knowledge? Some women look with trepidation upon the potential of planning their life in view of a risk, while others believe that only through knowledge and awareness we can improve control of our life. The risk of breast cancer may be qualitatively so important to justify all the potential risks of finding out about it.

Genetic testing for cancer predisposition.

Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.

Costs and benefits of diagnosing familial breast cancer.

Based on results from our surveillance program for women at risk for inherited breast cancer, we have calculated cost per year earned. Norwegian National Insurance Service reimbursement fees were used in the calculations. The calculated costs are based on empirical figures for expanding already established medical genetic departments and diagnostic outpatient clinics to undertake the work described. Cost per year earned was estimated at Euro 753 using our current practice of identifying the high-risk women through a traditional cancer family clinic. A strategy of identifying the high-risk families through genetic testing of all incident breast and ovarian cancers for founder mutations in BRCA1, will increase the cost to Euro 832. Costs related more to genetic counseling and clinical follow-up than to laboratory procedures. This potential economic limiting factor coincides with a shortage of personnel trained in genetic counseling. The number of relatives counseled to identify one healthy female mutation carrier (i.e. the uptake of genetic testing) is more important to cost-effectiveness than family size. Costs will vary depending upon the penetrance of the mutations detected and the prevalence of founder mutations in the population examined. Prevalences of BRCA1 founder mutations in some high incidence areas of Norway may be sufficiently high to consider population screening. Unlike mutation screening of cancer genes, founder mutation analysis will not identify DNA variants of uncertain clinical significance. Identification of high-risk families through founder mutation analysis of BRCA1 ensures that families with maximum risks are given first access to the limited resources of the high-risk clinics. This may be the greatest contribution to increased cost effectiveness of such a strategy. The assumptions underlying the calculations are discussed. The conclusion is that inherited breast cancer may be managed effectively for the cost of Euro 750-1,600 per year earned.