Clinical Impact of Constitutional Genomic Testing on Current Breast Cancer Care.

The most commonly diagnosed cancer in women worldwide is cancer of the breast. Up to 20% of familial cases are attributable to pathogenic mutations in high-penetrance (BReast CAncer gene 1 [BRCA1], BRCA2, tumor protein p53 [TP53], partner and localizer of breast cancer 2 [PALB2]) or moderate-penetrance (checkpoint kinase 2 [CHEK2], Ataxia-telangiectasia mutated [ATM], RAD51C, RAD51D) breast-cancer-predisposing genes. Most of the breast-cancer-predisposing genes are involved in DNA damage repair via homologous recombination pathways. Understanding these pathways can facilitate the development of risk-reducing and therapeutic strategies. The number of breast cancer patients undergoing testing for pathogenic mutations in these genes is rapidly increasing due to various factors. Advances in multigene panel testing have led to increased detection of pathogenic mutation carriers at high risk for developing breast cancer and contralateral breast cancer. However, the lack of long-term clinical outcome data and incomplete understanding of variants, particularly for moderate-risk genes limits clinical application. In this review, we have summarized the key functions, risks, and prognosis of breast-cancer-predisposing genes listed in the National Health Service (NHS) England National Genomic Test Directory for inherited breast cancer and provide an update on current management implications including surgery, radiotherapy, systemic treatments, and post-treatment surveillance.

[Metastatic castration-resistant prostate cancer and PARP inhibitors: From tumor genomics to new therapeutic combinations]. / Cancer de prostate métastatique résistant à la castration et inhibiteurs de PARP : de la génomique tumorale aux nouvelles associations thérapeutiques.

Castration-resistant metastatic prostate cancer remains lethal and a therapeutic challenge. Current strategies are geared towards the personalization of treatments based on the identification of relevant molecular targets, including genomic alterations involved in tumoral processes. Among these novel targeted therapies, poly-ADP-ribose polymerase inhibitors (PARPi), by blocking the action of enzymes involved in deoxyribonucleic acid (DNA) repair, induce the destruction of cells carrying defects in homologous recombination repair, often associated with alterations in genes involved in this mechanism. Thus, determining the presence of a molecular anomaly, particularly alterations in the BRCA1/2 genes, is a prerequisite for initiating PARPi monotherapy. In patients with metastatic castration-resistant prostate cancer , around 20-30 % carry this type of mutation. In this population, single-agent studies have demonstrated PARPi ability to prolong overall survival, and to improve symptom control, including pain. Other studies are underway to assess their effectiveness in combination with other therapies, and it already appears that association with new-generation hormone therapy can further prolong radiological progression-free survival, regardless of the mutation status of the genes involved in DNA repair, indicating a synergistic action between PARPi and new-generation hormone therapy.

Ethical considerations in prenatal genomic testing.

This paper discusses ethical issues arising in the context of prenatal genomic testing. While genomic information in the prenatal context might increase reproductive choice, e.g. to better understand a phenotype detected during screening, the availability of ever broader screens, even in the absence of a suspicion of abnormality, will generate increasingly complex and uncertain information. This raises questions of how much and what information should be provided prior to testing and what information should be returned (and to whom) once testing has been performed. As prenatal genomic testing becomes broader and more routine, the information generated will have more often implications not only for the fetus, but also for the parents, siblings and the wider family, raising questions about professionals' responsibilities. Further challenges discussed in this paper include access to genomic testing and justice, as well as ongoing management and post-pregnancy follow-up. The paper highlights the importance of taking into account the particular difficulties that arise in the context of prenatal genomic testing: the uncertainty of the information while choices are binary (to continue with or to terminate pregnancy); the time pressure due to the statutory limits on the availability of termination; and the impact the testing of the fetus has on the woman's body and life.

A case of colon cancer implanted on endoscopic resection ulcer certified by cancer genomic testing.

A 90 year-old man underwent endoscopic mucosal resection for lesions in the descending and sigmoid colons as well as endoscopic submucosal dissection (ESD) for a lesion in the rectal peritoneal reflection (Ra) 1 month before undergoing laparoscopic resection and D3 dissection for advanced cancer in the descending colon. One year later, he underwent a surveillance colonoscopy, and advanced colorectal cancer was detected on the ESD scar. The history suggested that this newly detected recurrent colorectal neoplasm on the ESD scar may have originated from cancer cells derived from the descending colon cancer that were implanted in the ESD ulcer, thereby initiating a new colorectal neoplasm. Cancer genomic testing further indicated that three of the four pathogenic variants detected in the recurrent colorectal neoplasm were consistent with pathogenic variants of descending colon cancer. This finding strongly supports our contention that cancer cells derived from the descending colon cancer were implanted in the post-ESD ulcer of the rectal Ra and proliferated, forming the recurrent colorectal neoplasm. This case report highlights the potential for tumor cell implantation on endoscopic resection ulcers and the utility of cancer genomic testing in validating this phenomenon.

Melanoma genomics - will we go beyond BRAF in clinics?

In the era of next-generation sequencing, the genetic background of cancer, including melanoma, appears to be thoroughly established. However, evaluating the oncogene BRAF mutation in codon V600 is still the only companion diagnostic genomic test commonly implemented in clinics for molecularly targeted treatment of advanced melanoma. Are we wasting the collected genomic data? Will we implement our current genomic knowledge of melanoma in clinics soon? This question is rather urgent because new therapeutic targets and biomarkers are needed to implement more personalized, patient-tailored therapy in clinics. Here, we provide an update on the molecular background of melanoma, including a description of four already established molecular subtypes: BRAF+, NRAS+, NF1+, and triple WT, as well as relatively new NGS-derived melanoma genes such as PREX2, ERBB4, PPP6C, FBXW7, PIK3CA, and IDH1. We also present a comparison of genomic profiles obtained in recent years with a focus on the most common melanoma genes. Finally, we propose our melanoma gene panel consisting of 22 genes that, in our opinion, are "must-have" genes in both melanoma-specific genomic tests and pan-cancer tests established to improve the treatment of melanoma further.

Molecular analysis of non-small cell lung cancer using a dual-targeted DNA and RNA comprehensive genomic profiling panel.

BACKGROUND: Comprehensive cancer genomic profiling tests have recently been used clinically to guide optimal treatment. Currently approved tests use DNA from tissue or plasma samples to analyze a few hundred genes. RNA panels complement DNA panels to detect fusion and exon skipping. METHODS: Between April 2017 and March 2022, we analyzed non-small cell lung cancer samples using Todai OncoPanel, a matched tumor/normal pair panel targeting both DNA and RNA. Publicly available genomic data was downloaded from the Center for Cancer Genomics and Advanced Therapeutics database on 2022/11/3. RESULTS: Sixty non-small cell lung cancer (NSCLC) samples were analyzed. With the DNA panel, 32 samples (53%) had TP53 loss-of-function mutations. Among adenocarcinoma, 17 (33%) had EGFR activating mutations, and 6 (12%) had ERBB2 activating mutations. One BRCA1 and one BRCA2 pathogenic germline variant were also detected. With the RNA panel, 11 fusion genes were detected, all in adenocarcinoma. Specifically, EML4-ALK and KIF5B-RET were detected from one sample each, and 9 others were all novel fusions with unknown pathogenicity. In addition, 4 of 60 (7%) NSCLC samples harbored MET exon 14 skipping. Analysis of the Center for Cancer Genomics and Advanced Therapeutics database found 37 MET exon 14 splice site mutations in 1514 NSCLC samples (2%, p = 0.039). CONCLUSIONS: Analysis of NSCLC with Todai OncoPanel detected many druggable targets. Its RNA panel may detect MET exon 14 skipping with high sensitivity.

Equitable Access to Genomic Molecular Testing for Australian Cancer Patients: Insights from the Victorian Precision Oncology Summit.

The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.

Shaping the future of kidney genetics in Australia: proceedings from the KidGen policy implementation workshop 2023.

The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.

Implementation and Evaluation of a National Multidisciplinary Kidney Genetics Clinic Network Over 10 Years.

Introduction: Diagnostic genomic sequencing is the emerging standard of care in nephrology. There is a growing need to scale up the implementation of genomic diagnostics nationally to improve patient outcomes. Methods: This pragmatic study provided genomic or genetic testing to patients with suspected monogenic kidney disease through a national network of kidney genetics clinics (KGCs). We sought to evaluate the experiences of implementing genomic diagnostics across Australia and associated diagnostic outcomes between 2013 and 2022. Results: We successfully established and expanded a nationwide network of 20 clinics as of 2022; concurrently developing laboratory, research, and education programs to scale the clinical application of genomics in nephrology. We report on an Australian cohort of 1506 kidney patients, of whom 1322 received their test results. We assessed barriers to implementation in the nephrology context, and where possible, applied real-time solutions to improve clinical processes over 10 years. Conclusion: Developing a multidisciplinary kidney genetics model across multiple health services nationally was highly successful. This model supported optimal care of individuals with monogenic kidney disease in an economically responsible way. It has continued to evolve with technological and service developments and is now set to scale further as genomic testing for kidney patients transitions to health care system funding.

Revisiting Utility of Fetal Autopsy in Genomic Era.

Background: Autopsy has been a gold standard in cases of antenatal detected anomalies or fetal demise. This helped clinicians in getting insights into the future management. In current times, ultrasound and genomic testing has become extremely powerful in further refining the etiological basis; however, fetal autopsy still has its role even now. Material and Methods: We have discussed the utility of fetal autopsy in current times by diving the cases in seven groups. Results: Case based discussions to discuss the utility of fetal autopsy. Conclusions: We suggest that fetal autopsy should be the standard of care in case of any abnormal fetal outcomes alongwith fetal genomic testing. Fetal autopsy is complementary to the ultrasound assessment and genomic investigations in reaching the final diagnosis and provides invaluable information regarding recurrence risk which may not be available when couple plans next pregnancy.

Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Current status and future of genomics in fetal and maternal medicine: A scientific review commissioned by European Board and College of Obstetrics and Gynaecology (EBCOG).

This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

Is Tunisia ready for precision medicine? Challenges of medical genomics within a LMIC healthcare system.

As one of the key tools on the precision medicine workbench, high-throughput genetic testing has enormous promise for improving healthcare outcomes. Tunisia has made tremendous progress in acquiring and implementing the technology in the clinical context. However, current utilization does not ensure the whole range of benefits that high-throughput genomic testing provides which impedes the country's ability to move forward into the new era of precision medicine. This issue is primarily related to the current state of Tunisia's healthcare ecosystem and the sociological attributes of its population, creating numerous challenges that must be addressed. In the current review, we aimed to identify and highlight these challenges that may be prevalent in other low and middle-income countries. Essentially, they fall into three main categories that include the socio-economic landscape in Tunisia, which prevents citizens from engaging in precision medicine activities; the current settings of the healthcare system that lack or miss key components for the successful implementation of precision medicine practices; and the inability of the current infrastructure and resources to handle the various challenges related to genomic data and metadata. We also propose five pillar solutions as a framework for addressing all of these challenges, which could strengthen Tunisia's capability for effective precision medicine implementation in today's clinical environment.

The Evolving Role of Genomic Testing in Early Breast Cancer: Implications for Diagnosis, Prognosis, and Therapy.

Multigene prognostic genomic assays have become indispensable in managing early breast cancer (EBC), offering crucial information for risk stratification and guiding adjuvant treatment strategies in conjunction with traditional clinicopathological parameters. The American Society of Clinical Oncology (ASCO) guidelines endorse these assays, though some clinical contexts still lack definitive recommendations. The dynamic landscape of EBC management demands further refinement and optimization of genomic assays to streamline their incorporation into clinical practice. The breast cancer community is poised at the brink of transformative advances in enhancing the clinical utility of genomic assays, aiming to significantly improve the precision and effectiveness of both diagnosis and treatment for women with EBC. This article methodically examines the testing methodologies, clinical validity and utility, costs, diagnostic frameworks, and methodologies of the established genomic tests, including the Oncotype Dx Breast Recurrence Score®, MammaPrint, Prosigna®, EndoPredict®, and Breast Cancer Index (BCI). Among these tests, Prosigna and EndoPredict® have at present been validated only on a prognostic level, while Oncotype Dx, MammaPrint, and BCI hold both a prognostic and predictive role. Oncologists and pathologists engaged in the management of EBC will find in this review a thorough comparison of available genomic assays, as well as strategies to optimize the utilization of the information derived from them.

Where there is no genetic counselor: An online decision-aid supports the majority of parents' diagnostic genomic testing choices for their children.

PURPOSE: We evaluated DECIDE, an online pretest decision-support tool for diagnostic genomic testing, in nongenetics specialty clinics where there are no genetic counselors (GCs). METHODS: Families of children offered genomic testing were eligible to participate. Fifty-six parents/guardians completed DECIDE at home, at their convenience. DECIDE includes an integrated knowledge quiz and decisional conflict screen. Six months later, parents were offered follow-up questionnaires and interviews about their experiences. RESULTS: Forty parents (71%) had sufficient knowledge and no decisional conflict surrounding their testing decision, but 6 of this group had residual questions. These 6, plus 16 with decisional conflict or insufficient knowledge, saw a GC. At follow-up, little-to-no decisional regret and few negative emotions were identified in any parents. Most chose testing and described their decision as easy, yet stressful, and described many motivations for sequencing. Parents appreciated the simple comprehensive information DECIDE provided and the ability to view it in a low-stress environment. CONCLUSION: DECIDE provides adequate decision-support to enable most parents to make value-consistent choices about genetic testing for their child. Parents reported that DECIDE helped to clarify motivations for pursuing (or declining) testing. DECIDE is a timely, well-tested, and accessible tool in clinical settings without GCs.

Evaluating parental personal utility of pediatric genetic and genomic testing in a diverse, multilingual population.

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings.

Attitudes, knowledge, and risk perceptions of patients who received elective genomic testing as a clinical service.

PURPOSE: Elective genomic testing (EGT) is increasingly available clinically. Limited real-world evidence exists about attitudes and knowledge of EGT recipients. METHODS: After web-based education, patients who enrolled in an EGT program at a rural nonprofit health care system completed a survey that assessed attitudes, knowledge, and risk perceptions. RESULTS: From August 2020 to April 2022, 5920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person but more often rated their risk for a heart attack as higher rather than lower than the average person (all P < .001). CONCLUSION: Patients pursued EGT because of the utility expectations but often misunderstood the test's capabilities.

Familial communication and cascade testing following elective genomic testing.

Familial communication of results and cascade genetic testing (CGT) can extend the benefits of genetic screening beyond the patient to their at-risk relatives. While an increasing number of health systems are offering genetic screening as an elective clinical service, data are limited about how often results are shared and how often results lead to CGT. From 2018 to 2022, the Sanford Health system offered the Sanford Chip, an elective genomic test that included screening for medically actionable predispositions for disease recommended by the American College of Medical Genetics and Genomics for secondary findings disclosure, to its adult primary care patients. We analyzed patient-reported data about familial sharing of results and CGT among patients who received Sanford Chip results at least 1 year previously. Among the patients identified with medically actionable predispositions, 94.6% (53/56) reported disclosing their result to at least one family member, compared with 46.7% (423/906) of patients with uninformative findings (p < 0.001). Of the patients with actionable predispositions, 52.2% (12/23) with a monogenic disease risk and 12.1% (4/33) with a carrier status reported that their relatives underwent CGT. Results suggest that while the identification of monogenic risk during elective genomic testing motivates CGT in many at-risk relatives, there remain untested at-risk relatives who may benefit from future CGT. Findings identify an area that may benefit from increased genetic counseling and the development of tools and resources to encourage CGT for family members.

Practical considerations for pathological diagnosis and molecular profiling of cholangiocarcinoma: an expert review for best practices.

INTRODUCTION: Advances in precision medicine have expanded access to targeted therapies and demand for molecular profiling of cholangiocarcinoma (CCA) patients in routine clinical practice. However, pathologists face challenges in establishing a definitive intrahepatic CCA (iCCA) diagnosis while preserving sufficient tissue for molecular profiling. Additionally, they frequently face challenges in optimal tissue handling to preserve nucleic acid integrity. AREAS COVERED: This article first identifies the challenges in establishing a definitive diagnosis of iCCA in a lesional liver biopsy while preserving sufficient tissue for molecular profiling. Then, the authors explore the clinical value of molecular profiling, the basic principles of single gene and next-generation sequencing (NGS) techniques, and the challenges in tissue sampling for genomic testing. They also propose an algorithm for best practice in tissue management for molecular profiling of CCA. EXPERT OPINION: Several practical challenges face pathologists during tissue sampling and processing for molecular profiling. Optimized tissue processing, careful tissue handling, and selection of appropriate approaches to molecular testing are essential to ensure that the highest possible quality of diagnostic information is provided in the greatest proportion of cases.

Epstein-Barr Virus Infection-Associated Facial Swelling: A Case Report.

Maxillofacial soft tissue swelling is a common clinical symptom with various etiologies. While odontogenic space infection is the most common cause, it is crucial not to overlook maxillofacial swellings caused by specific pathogenic infections and other local factors. This paper reports the case of an adult patient with right-sided swelling of his face, persistent oral mucosal ulcers, and recurrent hyperthermia for 30 days. He had received various antibiotics for the initial diagnosis of "right buccal space infection," but the antibiotics did not have any effect on his symptoms. None of the blood tests, histological examinations, bone marrow biopsies, and immune-related tests produced diagnostic findings. A diagnosis of Epstein-Barr virus (EBV) infection was finally confirmed by biopsy tissue genomics sequencing and quantitative analysis of EBV nucleic acid. In this report, we describe the diagnosis and treatment process for this patient and suggest that facial swelling could be an important clinical symptom of EBV infection.