Georgia L. Wiesner

Familial gastric cancer: overview and guidelines for management*

Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germlineE-cadherin/CDH1mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germlineE-cadherin/CDH1mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.

Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1 (refs 2–4), but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the ‘second genetic hit’ in the genesis of these cancers.

E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

To extend earlier observations of germline E‐cadherin mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, we searched for germline E‐cadherin mutations in five further families affected predominantly by diffuse gastric cancer and one family with a history of diffuse gastric cancer and early‐onset breast cancer. Heterozygous inactivating mutations were found in the E‐cadherin gene in each of these families. No mutation hotspots were identified. These results demonstrate that germline mutation of the E‐cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer. Hum Mutat 14:249–255, 1999.

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Disclaimer: The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider’s best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC “approve” or “endorse” any specific methods, practices, or sources of information.Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.Genet Med advance online publication 13 November 2014

A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2

Colorectal cancer is the second most leading cause of cancer death among adult Americans. Two autosomal dominant hereditary forms of the disease, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, together account for perhaps 5% of all cases. However, in ≈20% of additional colon cancer cases, the affected individuals report a family history of colon cancer in a first-degree relative. Similar familial clusters of colon cancer and early-onset colon adenomas have also been reported. To determine whether such familial aggregations arise by chance or reflect a hereditary colon cancer susceptibility, we conducted a whole genome scan to test for genetic linkage in 53 kindreds in which two or more siblings were affected by age 65 or younger with colon cancer or with advanced colon adenomas that were >1 cm in size or that showed high-grade dysplasia. In this cohort we found genetic linkage of disease (P = 0.00045) to chromosomal region 9q22.2-31.2 in a pattern consistent with autosomal dominant disease alleles. These data suggest that a single locus can contribute to disease susceptibility in a subset of patients with nonsyndromic forms of familial colorectal neoplasia.

Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers

Aberrant glycosylation is a pathological alteration that is widespread in colon cancer, and usually accompanies the onset and progression of the disease. To date, the molecular mechanisms underlying aberrant glycosylation remain largely unknown. In this study, we identify somatic and germ-line mutations in the gene encoding for polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) in individuals with colon cancer. Biochemical analyses demonstrate that each of the 8 GALNT12 mutations identified inactivates the normal function of the GALNT enzyme in initiating mucin type O-linked protein glycosylation. Two of these inactivating GALNT12 mutations were identified as acquired somatic mutations in a set of 30 microsatellite stable colon tumors. Relative to background gene mutation rates, finding these somatic GALNT12 mutations was statistically significant at P < 0.001. Six additional inactivating GALNT12 mutations were detected as germ-line changes carried by patients with colon cancer; however, no inactivating variants were detected among cancer-free controls (P = 0.005). Notably, in 3 of the 6 individuals harboring inactivating germ-line GALNT12 mutations, both a colon cancer and a second independent epithelial cancer had developed. These findings suggest that genetic defects in the O-glycosylation pathway in part underlie aberrant glycosylation in colon cancers, and they contribute to the development of a subset of these malignancies.

Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome

A cytogenetically visible interstitial deletion of chromosome band 10q23 was found in a 6‐year‐old boy with mental retardation, dysmorphic features, and juvenile polyposis coli. In order to map this patients deletion physically, we performed fluorescence in situ hybridization by using yeast artificial chromosomes (YACs) in the vicinity of the deletion. Five YACs that span an 11–15 cM region within the deletion were identified. This patients deletion contains the putative locus for Cowden syndrome and a recently discovered candidate tumor suppressor gene (MMAC1 or PTEN) that has been implicated in the progression of a variety of human malignancies. Furthermore, the deletion is near and possibly overlaps a locus associated with juvenile polyposis. The findings in this patient with a constitutional 10q23 deletion raise the issue of whether there are separate genes in this region that are involved in Cowden syndrome, Bannayan‐Riley‐Ruvalcaba syndrome, juvenile polyposis, and tumor progression, or whether all of these entities could be due to a single gene. Genes Chromosomes Cancer 21:113–118, 1998.

Identification of Barrett's Esophagus in Relatives by Endoscopic Screening

AIM:Familial aggregation of Barretts esophagus and its associated cancers has been termed familial Barretts esophagus (FBE). The aim of the study was to determine whether endoscopic screening would identify Barretts esophagus (BE) in relatives of probands with BE or esophageal adenocarcinoma (EAC).METHODS:All living first-degree relatives of patients with long segment BE or EAC presenting to the endoscopy suite of two academic hospitals were sent validated questionnaires inquiring about gastroesophageal reflux symptoms and prior endoscopic evaluation. First-degree relatives of affected probands or affected relatives who reported no prior upper endoscopy were offered screening unsedated esophagoscopy. Relatives with chronic gastroesophageal reflux symptoms were also offered an alternative of conventional sedated upper endoscopy. The yield of screening endoscopy was measured. Screening endoscopy findings were then compared between family members of known FBE patients and those with “isolated” disease.RESULTS:One hundred and ninety-eight relatives from 69 families, 23 known FBE probands and 46 probands with apparently “isolated” disease, were enrolled. Forty relatives (29 FBE relatives and 11 relatives of probands with “isolated” disease) reported prior upper endoscopy. Screening upper endoscopies performed on 62 (25 FBE and 37 “isolated” disease relatives) of the remaining 158 relatives identified Barretts epithelium in 13 (21%). Compared to probands with apparently “isolated” disease, Barretts epithelium (EAC, BE, or SSBE) was identified significantly more often in siblings and offspring of FBE probands, p≤ 0.05. Endoscopic screening of relatives of FBE probands identified a multigeneration multiplex FBE pedigree consistent with an autosomally dominant inherited trait. Endoscopic screening of relatives of probands with reported “isolated” diseased did not identify any new FBE pedigrees.CONCLUSIONS:Endoscopy identified EAC, long-segment BE, and short-segment BE in a substantial proportion of first-degree relatives of affected members of FBE families. A familial susceptibility to develop Barretts epithelium appears to be present in a subset of patients with BE and EAC.

IRB perspectives on the return of individual results from genomic research

Purpose:Return of individual research results from genomic studies is a hotly debated ethical issue in genomic research. However, the perspective of key stakeholders—institutional review board (IRB) professionals—has been missing from this dialogue. This study explores the positions and experiences of IRB members and staff regarding this issue.Methods:In-depth interviews with 31 IRB professionals at six sites across the United States.Results:IRB professionals agreed that research results should be returned to research participants when results are medically actionable but only if the participants want to know the results. Many respondents expected researchers to address the issue of return of results (ROR) in the IRB application and informed-consent document. Many respondents were not comfortable with their expertise in genomics research and only a few described actual experiences in addressing ROR. Although participants agreed that guidelines would be helpful, most were reticent to develop them in isolation. Even where IRB guidance exists (e.g., Clinical Laboratory Improvement Act (CLIA) lab certification required for return), in practice, the guidance has been overruled to allow ROR (e.g., no CLIA lab performs the assay).Conclusion:An IRB–researcher partnership is needed to help inform responsible and feasible institutional approaches to returning research results.Genet Med 2012:14(2):215–222

Cardiac disease in Costello syndrome

* Abbreviations: ECHO = : echocardiography • VSD = : ventricular septal defect • ECG = : electrocardiogram • HCM = : hypertrophic cardiomyopathy • PDA = : patent ductus arteriosus In 1977, Costello1described 2 patients with a new multiple congenital anomalies/mental retardation syndrome. Recently, additional reports of Costello syndrome have been published, bringing the number of patients described to near 30.2-18 Features of the syndrome include postnatal growth deficiency, mental retardation, cutis laxa, characteristic facies, papillomas, and various cardiac abnormalities.18 The syndrome is thought to be a result of sporadic autosomal dominant mutations, although the gene involved is unknown.19 Articles discussing Costello syndrome have consisted of single case reports or small series confined primarily to the genetics literature. This fact, coupled with the uncommon nature of the syndrome, has made it difficult to ascertain frequency, type, and natural history of the associated cardiac defects. It appears, however, that cardiac findings are clinically important and may be common. Moreover, the spectrum of heart disease is somewhat unique in that it includes not only congenital structural defects but also rhythm disorders and acquired obstructive cardiomyopathy. We present an infant with Costello syndrome whose cardiac diagnoses typify what has been variously described in this syndrome. We then review the literature to estimate the frequency and nature of heart disease in this group of children. Finally, we discuss how the spectrum of findings in Costello syndrome compare with other syndromes known to encompass heart disease. The male infant was the 4.2-kg product of a 35-week gestation. Fetal echocardiography (ECHO) had demonstrated a possible ventricular septal defect (VSD). After delivery, a small restrictive perimembranous VSD was confirmed. Frequent premature atrial contractions were seen on electrocardiogram (ECG). The postnatal course was complicated by hypotonia and poor feeding. At 2 months of age, he developed multifocal atrial ectopic tachycardia, with 1:1 conduction at a rate of 260 beats per minute. Normal sinus rhythm was restored with digoxin. At 11 months of age, …