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At least 19 recordsLinked to original sources
PubMed2026

Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.

BACKGROUND AND AIMS: Comprehensive genomic profiling (CGP) for tumors and germline genetic testing (GGT) inform precision therapy and clinical management of patients with colorectal cancer (CRC), and evidence is growing in support of universal paired CGP-GGT patient testing. However, the utility of combining CGP and GGT for early-stage CRC (ESC) and early-onset CRC (EOC) is unclear. METHODS: We performed a prospective, multisite study featuring GGT using an 80+ gene next-generation sequencing platform and exome-based CGP among CRC patients (unselected for age, stage, family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: A total of 150 CRC patients had GGT and exome-based CGP performed. ESC patients had an enrichment of high microsatellite instability and high tumor mutation burden. High microsatellite instability was also enriched in those with smoking history, and in tumors with mutated BRAF, homologous recombination deficiency, or at least 1 variant in the rat sarcoma virus pathway. Moreover, patients with smoking history were enriched in BRAF and other Tier 1 or 2 variants overall. Sixteen percent of patients harbored a pathogenic germline variant, most frequent being in Lynch syndrome genes. Paired GGT and CGP testing had high rates of clinically significant findings (≈70%) with the most frequent being high tumor mutation burden status. Pathway and mutational signature analysis revealed frequent CGP mutations in DNA repair and cell cycle pathways. CONCLUSION: These data suggest that universal, combined GGT-CGP increases clinical utility for EOC and ESC patients. This is key for EOC patients who tend to experience poorer outcomes. CGP-GGT expedites germline resolution for tumor mutations in hereditary cancer genes, reducing delays and facilitating identification of relevant therapies, clinical trials, and management recommendations.

Colorectal Cancer↗
PubMed2001

Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing.

BACKGROUND & AIMS: The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. METHODS: We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. RESULTS: Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. CONCLUSIONS: The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2003

[Human germline genetic tests].

A guideline for genetic testing by 10 scientific societies was published recently. This can be summarized as follows. 1) Generalized medical care for genetic medicine is necessary when genetic testing is considered. 2) Analytical validity, clinical validity and clinical usefulness must be proven when genetic testing is applied to clinical medicine. 3) Informed consent must be given by the client before genetic testing is performed. 4) Information on an individual's genetic test must be protected tightly and should not be disclosed to others without permission from the client. 5) Genetic counseling must be performed before genetic testing is performed. 6) The purposes of genetic test performed to prepositus ((i) for definite diagnosis of the patient and (ii) for obtaining information by predictive tests for family members) should be clearly distinguished. 7) Genetic tests for detection of carrier status of specific genetic conditions should be carefully performed, because they do not affect the health condition themselves, but can be a cause of discrimination. 8) Predictive genetic tests must be performed very carefully, especially when no procedures of treatment/prevention are available. 9) In general, genetic testing of children should be considered when such tests provide clinical benefits to the children themselves.

Forecasting↗
PubMed2026

Hereditary cancer: Germline testing practices across ERN GENTURIS member countries.

Germline genetic testing practices for hereditary cancer vary across the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) member countries. We surveyed experts in genetic testing from 20 EU member countries and Norway to assess multi-gene panel usage, availability of genome-wide sequencing, first-tier testing approaches, implementation of polygenic risk scores, and the roles of non-genetic healthcare professionals. National experts and members of the ERN GENTURIS completed a structured questionnaire covering founder germline pathogenic variants (gPV) testing, panel testing for common genetic tumour risk syndromes, use of whole-exome sequencing (WES) and whole-genome sequencing, polygenic risk score implementation, use of formalin-fixed paraffin-embedded tumour samples, laboratory accreditation, and the clinical roles of physicians, genetic counselors and nurses. Significant inter-country heterogeneity was observed. Most countries rely on next-generation sequencing (NGS) multi-gene panels. Founder gPV testing is first-line in a few high-prevalence populations (e.g., BRCA1/2 founders). All 21 countries offer NGS panel tests for hereditary breast and ovarian cancer, and ≥19 countries do so for colorectal and prostate cancers. However, NGS panel size and gene composition exhibit substantial variability. WES is available in 12 countries on a routine basis. Most countries implemented genetic testing on stored tumour tissue from deceased patients. In all countries, clinical geneticists can order germline genetic tests, and in 9 countries, any physician can do so. These findings show differences in accessibility to germline genetic testing of hereditary cancer in Europe. We propose EU-wide guidance via pathways, standards of care, and sharing of best practices to further optimize access to hereditary cancer genetic molecular diagnostics.

Humans↗
PubMed2025

Nonadherence to guidelines for genetic testing in families with ovarian cancer shows racial bias.

PURPOSE: The National Comprehensive Cancer Network (NCCN) recommends germline genetic testing for individuals at risk for hereditary ovarian cancer. We sought to determine the proportion and characteristics of individuals meeting testing criteria in a multicenter biobank who were appropriately offered testing. METHODS: In this retrospective cohort study, we identified Mass General Brigham Biobank participants meeting genetic testing criteria per NCCN guidelines. Logistic regression was used to analyze sociodemographic factors associated with which participants were offered testing, completed testing, and had a family history that matched their self-report documented in the electronic medical record. RESULTS: Most eligible participants (909/1441, 63.1%) were not offered genetic testing. Participants who were Black or Hispanic had a lower likelihood of being offered testing. Compared with self-report, 988 (68.6%) participants had a family history of ovarian cancer documented in their electronic medical record. Older age, Hispanic ethnicity, and public insurance use were associated with decreased likelihoods of accurate family history documentation. Correct documentation was associated with an increased likelihood of being offered testing. CONCLUSION: The majority of participants in this study did not receive NCCN-compliant care. Germline genetic testing for hereditary ovarian cancer screening is underutilized and access to this testing is currently inequitable.

Adult↗
PubMed2026

ACG Clinical Guideline: Diagnosis and Management of Adenomatous Colorectal Polyposis Syndromes.

The hereditary adenomatous colorectal polyposis syndromes are incurable, systemic, cancer risk predisposition syndromes with substantial morbidity and mortality. They differ in their mode of inheritance, age at disease onset, phenotypic expression, and cancer risk. The most common cancer risks involve the gastrointestinal tract including the colon, rectum, duodenum, ampulla, and stomach. Identifying these syndromes through personal and family history risk assessment and germline genetic testing, along with timely surgical and endoscopic management, can reduce cancer incidence and mortality. These guidelines use the Grading of Recommendations, Assessment, Development, and Evaluation methodology to provide clinical guidance on the selection of individuals who should undergo a risk assessment for a hereditary adenomatous colorectal polyposis syndrome, modality and timing of germline genetic testing, cancer risk mitigation through endoscopic and surgical interventions, and the role of chemoprevention. This document reviews the approach to genetic testing in patients with phenotypic colorectal polyposis and the impact of presymptomatic diagnosis in families with a known familial germline pathogenic variant or clinical features suggestive of a hereditary adenomatous polyposis syndrome. Management strategies for patients based on genetic test results or without genetic testing are provided. We also review colorectal and extracolonic phenotypic benign and malignant manifestations of the known hereditary syndromes with a focus on the 2 most common hereditary colorectal polyposis syndromes: familial adenomatous polyposis and MUTYH-associated polyposis. The document concludes with recommendations on polyposis and cancer risk mitigation strategies and highlights updates to management since the previous guideline was published.

Humans↗
PubMed1995

Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II.

OBJECTIVE: Multiple endocrine neoplasia, type II (MEN-II) is an autosomal dominant disorder characterized by tumors of thyroid C cells and pheochromocytoma. Recently, germline mutations in the RET proto-oncogene have been identified in patients with MEN-II. The aims of this study were (1) to define the mutations in clinically diagnosed MEN-II families, (2) to compare the results of genetic and biochemical testing, and (3) to evaluate the impact of mutation analyses for the members of these families. DESIGN: Register-based survey study of clinically affected and unaffected members of MEN-II families. SETTING: Register of families from Germany and Spain with pheochromocytomas. Two research laboratories at Cambridge University in the United Kingdom. PATIENTS: We investigated consenting affected and unaffected members belonging to a series of 10 families who met the clinical criteria for MEN-II. MAIN OUTCOME MEASURES: (1) Presence or absence of germline mutation in the RET proto-oncogene in affected and unaffected members of the 10 families, and (2) in the absence of RET mutation in a given family, presence or absence of germline mutation in the von Hippel-Lindau (VHL) gene, which is the susceptibility gene involved in a closely related syndrome, von Hippel-Lindau disease. RESULTS: In eight of these families, RET mutations were identified. The specific mutations were detected in all affected members. The remaining two families without RET mutations were subsequently shown to have a mutation within the VHL gene. The VHL mutations were identified in both families and represent a previously undescribed base change. After identification of the mutation, premorbid genetic testing was performed in all MEN-II and VHL families, resulting in detection of asymptomatic carriers in the MEN-II families. Clinically, the two VHL families differed from the eight MEN-II families by the presence of a C-cell tumor in only one individual from each family and extra-adrenal pheochromocytoma in three of nine affected individuals in the two families combined. CONCLUSIONS: The diagnosis of MEN-II should be confirmed by molecular genetic analysis and the diagnosis of VHL syndrome should be considered for families with an absence of RET mutations and a preponderance of pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed2002

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer.

PURPOSE: Identification of germline mutations in mismatch repair genes is increasingly being used to guide clinical practice in hereditary non-polyposis colon cancer. The aim of this study was to retrospectively assess the clinical utility of immunostaining and microsatellite instability testing in a group of individuals in whom germline testing of hMSH2 and hMLH1 had already been performed. METHODS: Individuals were identified from the records of family cancer clinics. A total of thirty-eight tumour blocks were retrieved from 28 kindreds. DNA was extracted and PCR amplification of six microsatellite markers was performed. Immunostaining was used to examine the expression of hMSH2 and hMLH1 protein. RESULTS: Of the 32 assessable tumours, 24 (75%) showed microsatellite instability. Most of the MSI-H cancers (92%) failed to express either hMLH1 or hMSH2. Deleterious germline mutations were identified in the proband in 12 of 28 families. Missense mutations were identified in 11 cases and no mutations in six probands. CONCLUSIONS: The use of germline genetic testing is indicated for a highly selected group of individuals. MSI testing and immunostaining are extremely useful tools which significantly improve the clinical interpretation of germline results. Ambiguity regarding the significance of missense mutations in hereditary bowel cancer suggests that these findings should be interpreted with caution.

Adaptor Proteins, Signal Transducing↗
PubMed2024

Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.

Adolescent↗
PubMed2026

Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a Patient with Small Cell Lung Cancer.

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.

Humans↗
PubMed2026

Hereditary Diffuse Gastric Cancer With Poorly Differentiated Gallbladder Adenocarcinoma: A Case Report Suggesting Carcinogenesis in the Stomach and Gallbladder Caused by a Pathogenic Germline Variant in CDH1.

BACKGROUND/AIM: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome primarily characterized by a high lifetime risk of diffuse gastric cancer and lobular breast cancer. It is predominantly caused by inactivating germline variants in the tumor suppressor gene CDH1. While the association between HDGC and these two specific malignancies is well-established, the co-occurrence of extra-gastric malignancies in other organs remains exceptionally rare. In particular, the clinical and genetic relationship between HDGC and gallbladder adenocarcinoma has not been previously clarified. CASE REPORT: We present the case of a 67-year-old female initially referred for surgical management of gallbladder cancer (GBC) following an initial cholecystectomy for progressive wall thickening. Pathological examination of the gallbladder revealed a de novo, poorly differentiated adenocarcinoma invading the subserosal layer with reduced E-cadherin expression. Given the atypical histopathology and a significant family history-her father and brother both died of gastric cancer at young ages-a preoperative gastric endoscopy was performed. The endoscopy identified multiple faded mucosal lesions, which biopsy confirmed as signet-ring cell carcinoma. The patient subsequently underwent total gastrectomy and gallbladder bed resection. Postoperative pathology identified 22 distinct malignant gastric lesions, predominantly signet-ring cell carcinoma (pT1a), showing variable or lost E-cadherin expression. Germline genetic testing via direct sequencing identified a pathogenic frameshift mutation in exon 5 of the CDH1 gene. CONCLUSION: This represents the first reported case of synchronous HDGC and primary gallbladder adenocarcinoma associated with a germline CDH1 mutation. Our findings suggest that pathogenic CDH1 variants may contribute to the carcinogenesis of poorly differentiated gallbladder adenocarcinoma. Clinicians should consider the possibility of extra-gastric malignancies in HDGC patients.

Humans↗
PubMed2026

Somatic-only SDHD variant with tumor-specific loss of heterozygosity in metastatic carotid body tumor: a case report with review of literature.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

Carotid body tumor↗
PubMed2026

Pathology-Driven Diagnosis of Hereditary Leiomyomatosis and Renal Cell Carcinoma: A Clinicopathological and Genetic Analysis of Three Cases.

INTRODUCTION: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant disorder characterized by three principal clinical features: cutaneous leiomyomas (cLMs), uterine leiomyomas, and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC). Although 200-300 families have been identified worldwide, its true prevalence remains unknown. CASE PRESENTATIONS: We present three HLRCC cases in which detailed pathological examination raised initial clinical suspicion. Cases 1 and 2 presented with advanced RCC exhibiting diverse morphologies. Case 3 presented with multiple painful cLMs and no renal tumors. All three cases were confirmed via germline genetic testing, which revealed distinct FH mutations. CONCLUSIONS: These cases underscore the importance of careful histopathological and immunohistochemical evaluation for the diagnosis of HLRCC. Multidisciplinary discussion integrating clinical, radiological, pathological, and genetic findings is essential for identifying affected families and initiating timely surveillance.

cutaneous leiomyoma↗
PubMed2025

Feasibility of using patient navigation to improve identification of hereditary cancer syndromes in newly diagnosed patients with colorectal cancer.

PURPOSE: Germline genetic testing to identify hereditary cancer syndromes in patients newly diagnosed with colorectal cancer (CRC) carries substantial benefits. We examined the feasibility of using patient navigation, an evidence-based approach to reduce structural barriers to recommended care, to improve test completion by increasing pretest counseling attendance. METHODS: We conducted key informant interviews with representatives from organizations providing cancer care to CRC patients. Interviews included questions derived from the Consolidated Framework for Implementation Research, which delineates barriers and facilitators to implementing evidence-based practices. We used an inductive-deductive coding approach to identify themes related to program feasibility. RESULTS: We interviewed 19 participants across 13 organizations. Key feasibility barriers included funding to implement and sustain a navigation program, staffing and supervising the navigator role, health information technology needs, gaining administrators' buy-in, and evolving genetic service delivery models. Participants suggested multiple strategies to address implementation barriers, but most would prefer other approaches to improve genetic test completion over implementing a genomics-focused patient navigation program. CONCLUSION: Stakeholders across a range of health care organizations saw limited value in improving the identification of hereditary CRC syndromes by implementing a program designed to increase pretest genetic counseling attendance. The need to scale up genetic testing has shifted interest toward delivery models better integrated in established care pathways, requiring fewer resources and providing broader reach.

Humans↗
PubMed2001

Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers.

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and > or = 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (> or = 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r = 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.

Adolescent↗
PubMed2003

The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications.

Basic studies of DNA replication and repair have provided surprising and pivotal insights into a novel pathway of tumorigenesis. Defects in the DNA mismatch repair process dramatically increase the risk for specific types of cancer because of instability in microsatellite DNA sequences. A germline mutation in either the hMSH2 or hMLH1 mismatch repair gene results in the hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch, syndrome. The lifetime risk for colon cancer is 80% in affected persons, and an aggressive cancer surveillance program is essential not only for these individuals but also for at-risk family members. The diagnosis of HNPCC can be made by fulfillment of the Amsterdam clinical criteria or through genetic testing for germline mutations in hMSH2 or hMLH1. Genetic testing is particularly useful in families with atypical clinical features and also for cancer risk assessment within an established HNPCC kindred. Microsatellite instability (MSI) of DNA is a hallmark feature of HNPCC-associated tumors, and as many as 15% of cases of sporadic colorectal cancer also display MSI. The biological behavior of colorectal tumors with MSI is distinctive; the most intriguing feature is their favorable natural history. The study of HNPCC has provided an example of the powerful interplay between molecular genetics and clinical care.

Base Pair Mismatch↗
PubMed2000

Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.

The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.

Adult↗
PubMed2000

Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.

BACKGROUND: Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. OBJECTIVE: To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. DESIGN AND METHODS: We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. SETTING: Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. PARTICIPANTS: Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. MAIN OUTCOME MEASURES: The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. RESULTS: Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. CONCLUSIONS: Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Adrenal Gland Neoplasms↗