Candidates For Genetic Testing Research Articles

Abstract PO4-09-02: Making a Case for Access to Genetic Testing in a Low Resource Country: A review of 313 Cases of MBC

Abstract Background Breast Cancer is the most common malignancy in Nigerian Women. It is responsible for the highest mortality amongst all malignant conditions. Breast cancer in Nigerian women typically presents at an earlier age and with a more aggressive tumour with triple negative molecular pattern in Nigerian women. These are usually some of the criteria for Genetic testing in the NCCN Guidelines. Due to resource challenges, Genetic testing is not readily available to Nigerian women We believe that if we can demonstrate that a high proportion of Nigerian women with breast cancer meet the criteria for Genetic Testing for Hereditary Breast and Ovarian Cancers, a case can be made for deploying resources towards Genetic Testing in this population of Women. Materials and Methods We collected prospective data about Nigerian Patients with Metastatic Breast Cancer as part of a UICC MBC Grant. We evaluated these patients for criteria for testing for breast cancer and present the result of our evaluation. Results Three hundred and Thirteen patients were recruited for this study. There were 2 male and 311 female. Twelve participants did not know their age, but 146 (40.3%) were younger than 45 years while 175 (55.9%) were older than 45 years. Twenty four (7.7%) had bilateral breast cancer while the 289 (92.3%) had unilateral breast cancer. One hundred and sixty two (54.8%) participants were triple negative, 124 of whom were 60 years or younger. In total, out of 313 participants, 202 (64.5%) patients were candidates for Genetic testing in a cohort of Metastatic Breast Cancer patients in Nigeria. Conclusion Various Indications for Genetic Testing in a cohort of Nigerian patients with breast cancer exists in more than 60% of patients. Considering the importance of PARP inhibitors in the management of breast cancer and implications for family members of these patients. It is important that cost appropriate genetic testing is made available to this group of breast cancer patients. Table. Risk Factors for Genetic Testing in Nigerian Patients Citation Format: Adewumi Alabi, AbdulRazzak Lawal, Tolulope Falowo, Olamijulo Fatiregun. Making a Case for Access to Genetic Testing in a Low Resource Country: A review of 313 Cases of MBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-02.

A randomized controlled trial evaluating pretest cancer genetics educational video or in-person genetic counseling.

10597 Background: Cancer genetic testing indications are rapidly expanding to determine treatment eligibility for patients with cancer, to identify individual cancer risk as well as to select family members at higher cancer risk when a pathogenic variant (PV) has been identified in the family. Currently, international guidelines recommend that all candidates for genetic testing should have genetic counseling to make an informed decision for genetic testing. However, with the increased demand for genetic testing, innovative ways to deliver pretest information are needed, especially in limited resource settings, where genetic cancer professionals’ availability is scarce. Methods: This is a non-inferiority trial comparing a pretest educational video to in-person genetic counseling. Participants referred for genetic cancer risk assessment at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were enrolled if they met international cancer genetic testing criteria and did not previously have genetic testing and/or counseling. The primary outcome was the uptake of genetic testing. Secondary outcomes included changes in genetic cancer knowledge, anxiety, and satisfaction using validated tools. Results: A total of 250 participants were included: 124 were randomized to the in-person genetic counseling arm and 126 to the educational video arm. Mean age was 47.9 years (SD 12.7), 86.4% were women, 37.2% had high-school or less and 86.4% had personal history of cancer (70% breast cancer). Overall, test acceptance was 100% in both arms. Cancer genetics knowledge improved in both groups: in-person from. 53 to .74 (diff .20; 95%CI .24-.26; p < 0.05) and video from .51 to .68 (diff .16; 95%CI .20-.12; p < 0.05). However, the in-person arm had a higher post counseling knowledge score (p 0.001). 43.5% and 42% of participants in the in-person and video arms had moderate-severe baseline anxiety. After intervention, both groups had a decrease in anxiety score: in-person from 5.2 to 4.7 (diff .58; 95% CI .09-1.08; p 0.01) and video from 4.9 to 4.1 (diff .75; 95%CI 0.42-1.08; p < 0.05). Both groups were satisfied with genetic services (97.5% and 92.5%, respectively; p 0.34). Conclusions: A pretest educational video was non-inferior regarding genetic testing acceptance. It was also associated with improved genetic cancer knowledge and decreased anxiety levels. These results support the use of educational videos before genetic testing where in-person genetic counseling availability is limited. Clinical trial information: pending .

The spectrum of Alpha and Beta Thalassemia Mutations: A 10-year Population-based Study of the Premarital Health Screening Program in West of Iran

Background: In various cancers, Ganoderic Acid A (GAA), an active triterpenoid derived from Ganoderma Background: Thalassemia refers to a category of inherited disorders resulting from defects in synthesizing one or several chains of hemoglobin (Hb). The present study aimed to determine the frequency of alpha and beta-thalassemia mutations in Kurdistan province, Iran.
 Materials and Methods: In this retrospective cross-sectional study, the laboratory data of 340 patients with thalassemia (170 females and 170 males), who were candidates for genetic testing in Kurdistan province, were examined over ten years (2006-2016). The participants were Kurd couples selected from the premarital health screening program.
 Results: In this demographic study, 20 beta mutations and nine alpha mutations were identified. Among the beta-thalassemia mutations, intervening sequence or intron No. 2- first nucleotide change as splice site mutation (IVS-II-1) (26.1%), codons 8/9 (14.8%), and intervening sequence or intron No. 1- first nucleotide (IVS-I-1) (12.2%) change as splice site mutation), had the highest frequency rates, respectively, constituting 53% of the beta mutations. In addition, α3.7(82.7%), -α4.2(8.3%), and --MED (Mediterranean deletion) (3.75%) were the most frequent alpha mutations, which constituted more than 90% of the alpha mutations.
 Conclusion: According to the results, the most frequent mutations in the HBB gene are IVS-II-1, Codons 8/9, and IVS-I-1, and in the HBA gene are α3.7, -α4.2, and –MED in Kurdistan province. In addition, the role of race and ethnicity as significant, influential factors in thalassemia was observable in the findings. The obtained results also indicated the communication pattern between the studied region's populations. Identifying common thalassemia mutations in an area could greatly benefit the early detection of thalassemia carriers in genetic laboratories and enhance thalassemia prevention programs.

Genetic counselling and testing for breast and ovarian cancer in Asia: A multinational survey of unmet needs.

10586 Background: Enabling equitable access to healthcare services among women remains a challenge in Asia. Differences in the presentation and treatment stage contribute to disparities in cancer outcomes. Genetic testing provides accurate risk assessment to help guide personalised preventative and treatment options. However, there is a critical need for research to further our understanding of barriers in leveraging optimal benefits of genetic testing and counselling (GT&C) to address cancer among women. Methods: A team of multinational experts was assembled to form the Asian Consensus and Recommendations on Genetic Testing and Counselling (ACROSS) Consortium to assess the challenges in adoption of GT&C for patients with breast and ovarian cancer in Asia. Critical publications were identified, and a pre-meeting questionnaire was developed. The questionnaire was refined to align with the objectives over iterations, and final approval was obtained from the steering committee. Survey responses were gathered from oncologists from ten countries across Asia. The expert committee discussed the survey results to highlight (1) current knowledge, attitude, and practices; (2) unmet needs and gaps; and (3) recommendations for addressing critical obstacles. Results: Adoption of GT&C for cancer is low in Asia. Lack of time, resources, and access to genetic counsellors are major difficulties faced. In most cases, the practising oncologists provide pre-test genetic counselling and communicate test results. For breast cancer (BC), most experts preferred germline testing only, with few opting for somatic testing if germline testing was negative. The agreement was lower among the ovarian cancer (OC) experts, with advocates for either germline or somatic testing or both. There was a lack of consensus on clinical criteria for selecting suitable candidates for genetic testing and the use of multiple gene panel germline testing. The need for government-aided subsidies and training programmes was highlighted. Conclusions: Recommendations from the expert panel included (1) development of guidelines and criteria to identify candidates suitable for GT&C; (2) training healthcare professionals with required competencies; (3) improving accessibility and affordability; (4) increased patient education and awareness; and (5) adoption of GT&C into the national healthcare system. The consortium agreed that a multifaceted plan of action combining the expertise of clinicians, scientists, and policymakers is required to facilitate uptake of GT&C in Asia. [Table: see text]

Germline pathogenic variants among Mexican patients with adenocarcinoma of the pancreas.

540 Background: The reported frequency of germline pathogenic variants (PVs) in patients with pancreatic cancer is 8-10%. Depending on the setting, pancreatic cancer-associated germline PVs in the BRCA and CDKN2A genes are the most commonly detected. The mismatch repair genes (MMR; Lynch syndrome) , TP53, STK11, ATM and PALB2 are also associated with an increased risk of pancreatic cancer . The identification of PVs in patients with pancreatic cancer is important as there may be a benefit of targeted therapies, such as PARP inhibitors for cases with defective double strand break repair or response to immunotherapy with defective MMR and high tumor mutational burden. Additionally, identification of predisposing PVs can enable screening and prevention for other family members through cascade testing. According to international guidelines, all patients diagnosed with exocrine pancreatic cancer are candidates for genetic testing. However, there is an underrepresentation of ethnic/ racial minorities, including Hispanic patients, in genetic studies. Methods: Between April 2017 and May 2020, patients with diagnosis of pancreatic adenocarcinoma who were treated at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and enrolled in the international Clinical Cancer Genomics Community Research Network registry were included in this analysis. Genetic testing was performed by full sequencing of the following genes: BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, CDKN2A, BRIP1, RAD50, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2 and EPCAM, as well as multiplex ligation-dependent probe amplification for selected genes and BRCA1 ex9-12del (Mexican founder mutation) screening with a three-primer polymerase chain reaction. Pedigrees, clinical and demographic data were obtained from the clinical records. Results: Forty-two patients with a diagnosis of pancreatic adenocarcinoma were included, with a median age at diagnosis of 57 years (range, 43-79), and 23/42 (55%) were women. The proportion of cases with operable, unresectable and metastatic disease at diagnosis was similar (33.3% for each group). The frequency of PVs was 11.9% ( ATM n =2, TP53 n =1, PALB2 n =1 and CHEK2 n =1). With a median follow-up 20 months 29/42 patients had died at the time of analysis (69%), the median overall survival was 16 months (range 3-84 months). No PVs were detected in the 4/42 patients who met the definition of familial pancreatic cancer (9.5%). Conclusions: Our results confirm the presence of PVs in cancer susceptibility genes in Mexican patients with pancreatic cancer, which is similar to that reported in other populations. However, it is notable that no BRCA PVs were identified in this small sample, as they are the most common PV found in other populations. Given to the heterogeneity of the PVs identified, our study supports the use of multi- gene panel testing in Hispanic patients with pancreatic cancer.

Personalized Decision Making on Genomic Testing in Early Breast Cancer: Expanding the MINDACT Trial with Decision-Analytic Modeling.

BackgroundGenomic tests may improve upon clinical risk estimation with traditional prognostic factors. We aimed to explore how evidence on the prognostic strength of a genomic signature (clinical validity) can contribute to individualized decision making on starting chemotherapy for women with breast cancer (clinical utility).MethodsThe MINDACT trial was a randomized trial that enrolled 6693 women with early-stage breast cancer. A 70-gene signature (Mammaprint) was used to estimate genomic risk, and clinical risk was estimated by a dichotomized version of the Adjuvant!Online risk calculator. Women with discordant risk results were randomized to the use of chemotherapy. We simulated the full risk distribution of these women and estimated individual benefit, assuming a constant relative effect of chemotherapy.ResultsThe trial showed a prognostic effect of the genomic signature (adjusted hazard ratio 2.4). A decision-analytic modeling approach identified far fewer women as candidates for genetic testing (4% rather than 50%) and fewer benefiting from chemotherapy (3% rather than 27%) as compared with the MINDACT trial report. The selection of women benefitting from genetic testing and chemotherapy depended strongly on the required benefit from treatment and the assumed therapeutic effect of chemotherapy.ConclusionsA high-quality pragmatic trial was insufficient to directly inform clinical practice on the utility of a genomic test for individual women. The indication for genomic testing may be far more limited than suggested by the MINDACT trial.

P13.04 Should We Offer Germline Testing to All Patients With Lung Cancer? An Ethical Point of View

Previous works show that germline mutations explain a minority of Lung Cancer (LC) cases, some features are: young patients (pts), pts with double primary tumor, and cancer family history (CFH). Nonetheless, guidelines for genetic counseling (GC) or genetic testing (GT) has not been published. Criteria for GT in other oncological scenarios become broader since GT cost is decreasing. In some instances, such as ovarian and pancreatic cancer, all pts are candidates for GT regardless their age or cancer family history. In this work, we argue that all pts should be referred to GC, and we present advantages and disadvantages of this approach. We reviewed medical records of LC pts from jan2018-dec2019, since we started our Genetic cancer risk assessment service in Jan2018. We gathered clinical, familial and demographic information, and the current status of pts. We evaluated if LC pts would be candidates to GT according to their age or multiple primary tumors. Also, we evaluated the age and the diagnosis of relatives with cancer in order to evaluate if they met NCCN criteria for GT. We reviewed the rate of referral of LC pts to GC and we calculated the percent of pts who missed GC. Finally, we present arguments for and against GT in all LC pts. 75 pts were included for this analysis, 4 pts were excluded because medical records were unavailable. Mean age was 63y (SD 12). 45 pts (63%) were younger than 60y. 41 pts (58%) were smokers. 33 (47%) were females. Men used more tobacco than women (p 0.0001) but no other differences were significant. 36 pts (57%) met criteria for GT, and 23 (66%) were referred to genetics. So far, 43 pts (60%) were alive, among them, 20 pts (47%) were referred to GC. 10 deceased pts who met criteria for GT hadn’t GC. Germline mutations carriers must not exceed 10% of all LC pts according to previous reports, but pts carrying actionable variants could miss advantages, for them and their relatives, such as: adjust surveillance for other primary tumors, perform cascade testing in relatives and start early detection programs, undergoing risk reduction strategies, access to clinical trials or benefit of targeted therapies. Nonetheless, no evidence of this approach has been proved. It could represent a financial burden for patients or health care institutions; insurance companies could reject to cover GT because of lack of defined criteria. It could represent a risk for genetic discrimination in countries without laws protecting against this specific issue. It would be expected to find many Variants of Unknown significance (VUS) which could cause anxiety to pts and could be treated as pathogenic variants and expose pts to unnecessary interventions. Finally, since this is not a standard practice, it remains to show whether GT is useful for all LC pts, pts could be at least be counseled about this possibility.

The contemporary landscape of genetic testing and breast cancer: Emerging issues

The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct-to-consumer (DTC) approach that is entirely consumer-driven; or a hybrid, patient-initiated, provider-mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.

G-Nomic: a new pharmacogenetics interpretation software.

We present g-Nomic, a pharmacogenetics interpretation software that analyzes globally a prescribed medication taking into account the personal background genetics, drug–drug interactions, lifestyle, nutritional supplements, inhibitors, inducers, and other risks to analyze primary or secondary metabolism pathways. G-Nomic provides a set of recommendations describing the suitability of a given combination of drugs for each patient according to their genes and polymedication. G-Nomic is updated monthly including data from the new drugs to be included, their known interactions, and the relevant pharmacokinetic biomarkers. For the interactions, the list is curated manually, only keeping those with clinical relevance. For each drug, their FDA and EMA drug labels are accessed, to check for relevant enzymes and transport proteins that influence its pharmacokinetics, and for their ability to induce or inhibit other enzymes, particularly the CYP-450 system. When this information is not available, a PubMed search is made to look for these characteristics. In addition, a distinction is made between drugs and prodrugs. A query on the g-Nomic software begins with entering the medication by either their common or commercial name. Non-pharmacological substances can be also added or selected under “lifestyle habits”. The lifestyle list is dynamic, showing only the substances known to interact with the drugs that are currently selected, and includes herb compounds, such as St. John’s wort, as well as proper lifestyle substances such as grapefruit or cigarette smoking. The software provides a list of the genes classified as primary biomarkers as candidates for genetic testing, and a list of the interactions that have been detected. If genetic information is available then, or is made available at a later point, these results can also be entered and the software returns pharmacogenetics recommendations regarding specific genotypes. g-Nomic takes all the above-mentioned parameters in an easy and user-friendly tool making prescription safer.

Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion.

An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members' curated files. All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Presentation and Clinical Characteristics of Patients with Maturity Onset Diabetes of the Young (MODY) at Women and Children’s Hospital of Buffalo

Background: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes. It is rare, representing the final diagnosis in 1-2% of individuals with diabetes. In the pediatric cohort, it can be confused with type 1 diabetes. Clinical diagnosis is suspected in the case of hyperglycemia, lack of autoantibodies, and autosomal dominant transmission. This retrospective chart review evaluated the clinical presentation and characteristics of patients diagnosed with MODY by our practice with a goal of identifying patients that can be candidates for genetic testing. Methods: Using ICD10 codes for MODY, we performed a retrospective chart review of patients carrying MODY diagnosis confirmed by genetic testing, who received their care at the Diabetes Center at Women and Children’s Hospital of Buffalo. Results: We identified 10 subjects with confirmed genetic testing for MODY. Median age of presentation with hyperglycemia was 13.1 years (range of 3.6-17.3 years). Median HbA1c at presentation was 6.3% (range 6%-14%). While the initial referring diagnosis was elevated fasting BS (FBS) in 50% of subjects, FBS (mean 120±21 mg/dL) was abnormal for all but 1 subject at their first contact visit. All subjects had negative pancreatic autoantibodies. In our cohort, confirmatory testing was as follows: MODY2 (n = 6), MODY3 (n = 2), MODY 4 (n=1), and MODY5 (n=1). Three subjects were assigned a MODY diagnosis prior to genetic testing. Two were siblings with family history of maternal MODY2. The third subject had a history of polycystic kidney disease, septate uterus, and HbA1C in the prediabetes range. This subject was assigned a presumptive diagnosis of MODY 5 prior to genetic test. Conclusion: In our practice, all subjects with confirmed MODY diagnosis had negative pancreatic autoantibodies with most meeting criteria for prediabetes diagnosis. Clinicians should have a high index of suspicion for MODY in subjects who do not fit criteria for T1DM or T2DM. Disclosure L. Saadeh: None. L.D. Mastrandrea: Research Support; Self; Novo Nordisk Inc., AstraZeneca, Sanofi-Aventis. Advisory Panel; Self; Pediatric Diabetes Consortium. Other Relationship; Self; American Academy of Pediatrics. Advisory Panel; Self; JAEB Center For Health Research.

Compound Heterozygous Variants in the Coiled-Coil Domain Containing 40 Gene in a Chinese Family with Primary Ciliary Dyskinesia Cause Extreme Phenotypic Diversity in Cilia Ultrastructure.

Purpose: Primary ciliary dyskinesia (PCD) is a rare genetic disorder manifested with recurrent infections of respiratory tract and infertility. Mutations in more than 20 genes including the Coiled-Coil Domain Containing 40 (CCDC40) gene are associated with PCD. A Chinese proband with a clinical diagnosis of PCD was analyzed for mutations in these genes to identify the genetic basis of the disease in the family. The proband showed altered mucociliary clearance of the airways, various degree of hyperemia and edema of the mucous membrane, left/right body asymmetry, infertility and ultrastructural abnormality of cilia in both sperm and bronchioles.Methods: The DNA from the proband was analyzed for genetic variation in a subset of genes known to cause PCD using targeted next generation sequencing in order to understand the molecular and genetic basis of the PCD in present family. The result of targeted next generation sequencing has been validated by Sanger sequencing and q-PCR.Results: Targeted next-generation sequencing identified two novel mutations (c.1259delA and EX17_20 deletion) in CCDC40 gene that causes abnormal CCDC40 mRNA expression. These two novel variants cause disorganization of axoneme filaments, which resulted in reduction of sperm motility and phenotypic diversity in ultrastructure of cilia in the proband.Conclusion: These findings highlight the significance of the mutations in CCDC40 as novel candidates for genetic testing in PCD patients as well as the key role of ICSI treatment for the families affected by this ciliary dysmotility. Our findings showed that our work enriched the performance of cilia ultrastructure which were not previously reported in PCD patients.

Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population.

We investigated the prevalence of Lynch syndrome and Lynch-like syndrome among Japanese colorectal cancer patients, as there have been no credible data from Japan. Immunohistochemical analyses for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were carried out in surgically resected, formalin-fixed paraffin-embedded specimens obtained from 1,234 newly diagnosed colorectal cancer patients between March 2005 and April 2014. The presence/absence of the BRAF V600E mutation and hypermethylation of the MLH1 promoter was analyzed where necessary. Genetic testing was finally undertaken in patients suspected as having Lynch syndrome. By the universal screening approach with immunohistochemical analysis for mismatch repair proteins followed by analyses for the BRAF V600E mutation and MLH1 promoter methylation status, 11 (0.9%) of the 1,234 patients were identified as candidates for genetic testing. Out of the 11 patients, 9 (0.7%) were finally diagnosed as having Lynch syndrome; the responsible genes included MLH1 (n = 1), MSH2 (n = 4), EPCAM (n = 1) and MSH6 (n = 3). The remaining two patients (0.2%) were regarded as having Lynch-like syndrome, since biallelic somatic deletion of the relevant mismatch repair genes was detected in the absence of germline mismatch repair alterations. None of the cases was identified as having germline MLH1 epimutation. The prevalence of Lynch syndrome among all newly diagnosed cases of colorectal cancer in Japan is in the same range as that recently reported by studies in Western population. The prevalence of Lynch-like syndrome seems to be extremely low.

Case report and literature review. Prenatally Detected Non-Immune Atrioventricular Block and Maternal Arrhythmia - Case Presentation and Literature Review

Abstract Our clinical report describes a rare finding of a prenatally-detected congenital atrioventricular (AVB) block without associated maternal antibodies, which progressed from 1st/2nd degree AVB to complete heart block during second half of pregnancy. Obstetrical ultrasound at 12th week did not reveal any abnormalities and prenatal echocardiography (due to VSD in afamily member) at the 18th week of gestation detected 1st degree block, then bigeminy and bradycardia. Transplacental treatment with B-2-mimetics was introduced. The delivery was organized in a tertiary center and a pacemaker for the newborn baby was secured and implanted in 15th day of life. Currently the boy`s condition is good and stable. Before therapy with B-2-mimetics the mother underwent echocardiography and ECG which revealed clinically silent structural and conduction heart abnormalities. Literature findings suggest that parents of children with non-immune congenital or childhood AVB are more likely to carry clinically silent conduction abnormalities than general population. Given the corresponding findings in the mother and her son, they should be good candidates for genetic testing.

Lower prevalence of Lynch syndrome in colorectal cancer patients in a Japanese hospital-based population.

The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution. Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010, immunohistochemistry analyses for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability (MSI) testing for surgically resected, formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60years of age were undertaken. Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary. Seven patients were identified as candidates for genetic testing by mismatch repair protein loss (n=7) or MSI-H (n=6). Methylation of MLH1 was detected in one case. Three patients were diagnosed with Lynch syndrome, comprising 2.2% of the total colorectal cancer patients younger than 60years of age. The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations.

Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas.

The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first-degree relatives of 58 mutation carriers. Of 159 women who were contacted by the proband or other family member, only 14 made an appointment for genetic testing (9%). In contrast, among 32 relatives who were contacted directly by the genetic counselor, 27 came for an appointment (84%). This study suggests that for recruitment of relatives in the Bahamas, direct contact by counselor is preferable to using the proband as an intermediary.

Genetics, Genomics, and Oncology

Genetics, Genomics, and Oncology

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Previous reports of Fabry disease screening in dialysis patients indicate that α-galactosidase A activity alone cannot specifically and reliably identify appropriate candidates for genetic testing; a marker for secondary screening is required. Elevated plasma globotriaosylsphingosine is reported to be a hallmark of classic Fabry disease. The purpose of this study was to examine the usefulness of globotriaosylsphingosine as a secondary screening target for Fabry disease. This study screened 1453 patients, comprising 50% of the male dialysis patients in Niigata Prefecture between July 1, 2010 and July 31, 2011. Screening for Fabry disease was performed by measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration, by high-performance liquid chromatography. Genetic testing and genetic counseling were provided. A low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter) was observed in 47 patients (3.2%). Of these, 3 (0.2%) had detectable globotriaosylsphingosine levels. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with p.Y173X started enzyme replacement therapy. Subsequent screening of his family identified the same mutation in his elder sister and her children. Genetic testing for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the plasma lyso-Gb3 screen identified Fabry disease with high sensitivity (100%) and specificity (94.3%). Plasma globotriaosylsphingosine is a promising secondary screening target that was effective for selecting candidates for genetic counseling and testing and for uncovering unrecognized Fabry disease cases.

BRCA1/2 mutations and triple negative breast cancers.

Identifying breast cancer patients at increased risk for carrying a mutation in the BRCA1 and BRCA2 genes is an important objective in clinical practice. Although age at diagnosis, family history of breast and/or ovarian cancer, and ethnicity are all essential parameters to consider when assessing risk, there are limitations as to how well such factors accurately predict BRCA1/2 status, even when quantitative risk models are applied. Integrating information about triple negative (TN) disease may help refine these estimates. Among newly diagnosed breast cancer patients, fewer than 10% have a mutation in the BRCA1 or BRCA2 genes, and up to 20% present However, among BRCA1 mutation carriers at least one-third have TN breast cancers. In this paper, we review key studies that have assessed breast cancer cases with a known BRCA1/2 status and triple marker data. We also discuss how integrating such information into qualitative and quantitative risk assessments of BRCA1/2 carrier probability may improve the ability to identify women who are appropriate candidates for genetic testing. Identifying women at increased risk is critical as knowledge of mutation status may impact surgical and systemic treatment in newly diagnosed patients, as well as recommendations for ovarian cancer risk management.

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer

BackgroundThe heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation. MethodsWe tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995–1999 and 2002–2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA). ResultsAmong the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma. ConclusionsBRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.