Anu Chittenden

Sharing BRCA1/2 Test Results With First-Degree Relatives: Factors Predicting Who Women Tell

PURPOSE Patient communication with relatives about cancer genetic test results is the primary means for alerting those who may benefit from identification of hereditary risk. This study identifies factors predicting patterns of disclosure of BRCA1/2 test results to first-degree relatives (FDRs) among women tested in a clinical protocol. PATIENTS AND METHODS A total of 273 women completed a family communication measure 4 months after BRCA1/2 result disclosure. chi2 analyses and logistic regression models identified factors predicting sharing of the test result. RESULTS Most FDRs were informed of the participants test result by 4 months; female relatives were more likely to be informed than males. Tested women conveyed inconclusive results (variant or negative without known familial mutation) less frequently to their sisters than conclusive (positive/true negative) results (P = .03). Twenty-three percent of participants did not inform their father. Informing brothers was more likely when BRCA1/2 was inherited through paternal lineage (P = .04), but 29% of brothers were not informed. Women older than age 40 were less likely to share their result with their parents (P = .03) than were women < or = 40. Childrens ages influenced communication to offspring; most children were told. CONCLUSION Demographic, health-, and test-related factors predicted genetic test result communication to FDRs. Additional research investigating the full spectrum of discussion within families and motives for incomplete sharing of genetic test results with relatives may suggest strategies for providers and targeted educational interventions for patients to enhance family communication.

Genetic Testing for Hereditary Colorectal Cancer: Challenges in Identifying, Counseling, and Managing High-Risk Patients

a P p a i i w m wenty years ago, the main clinical application for genetic testing was in the prenatal and pediatric ettings. Currently, genetic testing plays an important ole in many areas of medicine, including gastroenterolgy. Genetic testing for cancer predisposition should be ffered when a patient has a personal or family history uggestive of a hereditary cancer syndrome and the geetic test will influence their own medical management nd/or that of their family members.1 Each year, nearly 40 000 people in the United States will be diagnosed ith colorectal cancer (CRC). Although most of these ases will be sporadic, estimates suggest that 5%– 6% of RCs develop as a result of inherited genetic mutations hat are associated with extremely high cancer risks reuiring specialized interventions for preventing cancer. linicians practicing in the genetics era are expected to 1) identify individuals who may be at risk for hereditary ancer syndromes, (2) ensure they undergo appropriate enetic evaluation, and (3) translate the information obained from genetic testing into effective clinical care. In his review, we examine indications for genetic testing for ereditary CRC syndromes and highlight some of the hallenges involved to reduce cancer mortality for these atients and their families. Clinical genetic testing is available for a number of ereditary gastrointestinal cancer syndromes, including amilial adenomatous polyposis (FAP), hereditary nonolyposis CRC/Lynch syndrome, Peutz-Jeghers synrome, and juvenile polyposis.2 The sensitivity of the ene tests can vary by syndrome. Approximately 90% of individuals with the classic polposis phenotype of 100s–1000s of colorectal adenomas ave germline mutations in the tumor suppressor gene PC, which can be detected through DNA sequencing nd/or deletion/duplication analysis using Southern blot r multiplex ligation-dependent probe amplification. Billelic mutations in the base-excision repair gene MYH an result in either classic polyposis or a more attenuated henotype of 10-100 colonic polyps. Because of the varibility in clinical presentation, American Gastroenterlogical Association guidelines recommend that individ-

Genetic testing by cancer site: breast.

Women in the United States have a 12% lifetime risk of developing breast cancer. Although only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene, individuals who carry a mutation in one of these genes have a significantly higher risk of developing breast cancer, as well as other cancers, over their lifetime compared with the general population. The ability to distinguish those individuals at high risk allows health care providers to intervene with appropriate counseling and education, surveillance, and prevention-with the overall goal of improved survival for these individuals. This article focuses on the identification of patients at high risk for breast cancer and provides an overview of the clinical features, cancer risks, causative genes, and medical management for the most clearly described hereditary breast cancer syndromes. Newer genes that have also been implicated in familial breast cancer are also briefly reviewed.

Ethical issues in cancer genetics: I 1) whose information is it?

This article presents and discusses four clinical cases that exemplify the complexity of ethical dilemmas concerning the provider’s obligation to disclose or withhold genetic information from patients.Case 1: What is the responsibility of the cancer genetics provider to ensure that a positive test results is shared with distant relatives?Case 2: To ensure that results go to at-risk relatives, do we have the right to ignore the wishes of the designated next-of-kin?Case 3: Do we have the right to reveal a familial BRCA1 mutation to a patient’s relative, who is at 50% risk?Case 4: Do we have an obligation to reveal that a patient is not a blood relative and therefore, not at risk to have inherited a familial mutation?These cases form the basis for discussing the provider’s dual obligations to keeping patient confidentiality and informing patients and families about risk (i.e. duty to warn). We also provide a summary of consensus points and additional discussion questions for each case.

Universal Screening for Mismatch-Repair Deficiency in Endometrial Cancers to Identify Patients With Lynch Syndrome and Lynch-like Syndrome.

Although consensus has yet to be reached on universal mismatch-repair (MMR) protein immunohistochemical (IHC) screening for Lynch syndrome (LS) in endometrial cancer (EC), an increasing number of institutions have adopted universal screening protocols similar to those used for colorectal carcinoma. Here we describe our institutions experience with a prospective universal screening protocol in which all ECs resected over a period of 19 months (n=242) were screened for MLH1, PMS2, MSH2, and MSH6 deficiencies using IHC, followed by MLH1 promoter methylation testing when appropriate. When consent was obtained, tumor samples underwent next-generation sequencing. A total of 11 unmethylated MMR-deficient cases (4.5% of cohort) were identified through IHC screening. Germline testing was performed in 10 cases and confirmed LS in 4 patients (1.7% of cohort). Of our 4 confirmed LS cases, 1 did not meet traditional LS screening criteria (eg, age below 50 y, Revised Bethesda criteria). In addition, universal screening identified 6 germline-negative MMR-deficient nonmethylated cases, 4 of which occurred in women older than 50. Although our next-generation sequencing data suggest somatic mutations in 4 of these cases, it is possible that these cases may represent cases of “Lynch-like syndrome.” We conclude that a subset of LS cases could be missed using traditional screening guidelines. The value of screening for Lynch-like syndrome has yet to be determined. Although the cost-effectiveness of universal screening in EC has yet to be elucidated, we conclude that universal IHC screening is currently a reasonable, and arguably superior, approach to screening for LS.

An American founder mutation in MLH1

Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589‐2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183–272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14–23); it accounts for 1.0% all LS in the Unites States and can be readily screened for.

Cancer Genetic Counseling

Our fundamental understanding of carcinogenesis has expanded dramatically over the past five years. Of foremost importance has been the discovery of genes that, when mutated in the germline, confer high risks of specific malignancies. The translation of these laboratory findings into clinical practice has led to the creation of a new medical subspecialty termed cancer genetic counseling. Cancer genetic counseling is defined as a communication process concerning an individual’s risk of developing specific inherited forms of cancer. This risk may be higher than or similar to the general population risks of cancer. Cancer genetic counseling can, but does not always, lead to genetic testing. The genetic counseling process involves: 1) obtaining detailed family, medical, and lifestyle histories; 2) documentation of cancer-related diagnoses; 3) pedigree analysis; 4) risk assessment and counseling; 5) general discussion of options for early detection and prevention; and 6) provision of genetic testing when appropriate. This chapter provides an overview of cancer genetic counseling, including a general description of the providers and patients involved, the cancer genetic-counseling process in a high-risk clinical setting and a predisposition-testing program, the provision of genetic counseling for selected hereditary-cancer syndromes, and case examples to highlight some of the complexities inherent to this process.

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

PurposeGermline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.MethodsUsing a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.ResultsWe found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05).ConclusionNearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Young Breast Cancer Patients Undergoing Breast-Conserving Therapy: Role of BRCA1 and BRCA2

Breast cancer is the most common cancer in women and the second leading cause of cancer-related death. In 2005, approximately 211,000 American women were diagnosed with invasive breast cancer and 40,000 died from the disease. 11,000 of these diagnoses were made in women under the age of 40 (American Cancer Society). BRCA1 and BRCA2 are tumor suppressor genes that are involved in multiple cellular processes including DNA repair and transcriptional regulation in response to DNA damage, chromosomal stability and cellcycle regulation (Kiyotsugu and Yoshio, 2004). Unlike classical tumor suppressor genes; however, mutations in BRCA1 and BRCA2 are almost never seen in sporadic breast cancers.

Breast Cancer Genetics and Risk Assessment

An accurate estimation of breast cancer risk is essential in guiding clinical management for women at all levels of risk. The goal of providing the appropriate clinical management is to increase survival in high-risk women and decrease cost and complications in low-risk women. Women can be at high risk of developing breast cancer based on benign disease (like ADH and LCIS) as well as family history of cancer. While the former is determined by the surgeon, the genetic counselor is essential in using the family history to distinguish those at high risk for breast cancer.