ACMG 2018 – “There is Still So Much We Have to Learn”

This year’s ACMG conference in Charlotte, North Carolina, included a very well received first installment of TED-style talks which reflected on the evolution and impact of healthcare. All three talks delivered by Kaylene Ready (Director of Inherited Cancer and a Genetics Counselor, Counsyl), Christian Schaaf (Professor Clinical Genomics, University of Cologne), and Wendy Chung (Associate Professor of Pediatrics, Columbia University Irving Medical Center) were inspirational, and were considered a great addition to ACMG 2018. Takeaways and key messages included: “treat every patient like patient No. 1, always keeping them at the center of the work, and us working as mediators rather than as a barrier”. Image credit: @DeniseCalvert13

Some statistical numbers were eye-opening and challenging as it comes as no surprise that the community currently lacks genetic counselors (GCs), with fewer than 4,000 GCs and 2,000s medical geneticists in the US which translates to one geneticist per ~60,000 people. With new genetic tests generated every day, GCs need to take on the role of mediators. New operational solutions were discussed to address this shortcoming, and as such Kaylene Ready proposed the exploration of chatbots as alternatives to GC service delivery. While certainly an interesting suggestion, we will have to see whether the field with its customers (i.e. patients) is ready to discuss challenging genetics findings with a computer. As a result, it was suggested to decouple genetic testing from genetic counseling with the aim to provide genetic counseling to those most in need of help with adaptation, coping, decision conflict, grief, understanding of complex results, family communication, and screening.

Some interesting quotes worth highlighting:

• Christian Schaaf: “Even in 2018, with exomes, genomes, and new technologies, we have 50% of the patients that walk into a clinic leave without a diagnosis.”
• Wendy Chung:
  • “There is still so much we have to learn.”
  • “We still have ways to go with interpretation.”
  • “Cloud-based collaborations can help with patient data sharing, collaboration, analysis consistency, improved quality, improved turn-around time, and decreased costs.”
• Heidi Rehm (Broad Institute): “You can’t have a pathogenic variant in a gene that has not been associated with a disease yet. Before variant classification, evidence is needed for the gene-to-disease association.”
• Les Biesecker (NIH): “The pathogenicity of a variant equals the likelihood that the variant is pathogenic, but it is not equivalent to the correctness of the diagnosis of the patient. Rather, subsequent lab assessment of pathogenicity is needed.”
• Kayla Hamilton (St. Jude Children’s Research Hospital): “10% of children with cancer had germline pathogenic variants identified on WES/WGS in multiple genes including one child with BRCA2. Family history was significant in hindsight.”
• Cheryl Reid (Aetna Better Health of New Jersey): “Insurers don’t buy genetic exceptionalism. We should have good evidence that tests are accurate and reliable. They want medical actions and they prefer tests with higher positive rates.”
• Steve Lincoln (Invitae): “9% of pathogenic variants are technically challenging to sequence, which affects test validation and sensitivity. It is a big problem to find positive controls for validation. Synthetic variant controls may be the answer.”
• Carlos Prada (Cincinnati Children’s):
  • “There is an alarming lack of clinical geneticists in the developing world – 1 per million people in Dominican Republic and Colombia – telemedicine consultations paired with local clinicians may be the answer.”
  • “Telegenetics to foreign countries achieved a diagnosis in ~64% of cases and changed management in ~50%; routine care established in ~20%.”

Following is a review of the different announcements that coincided with the conference spanning commercial product launches, new partnerships and collaborations, product integrations, and other interesting and relevant topics.

Genetic testing / precision medicine

• Geisinger execs: DNA sequencing program saving patient lives – Over time, as we sequence the exomes of our patients & learn even more about particular genome variants and their impact on health conditions, we predict that ~10-15% will benefit. With more than 90,000 people participating in Geisinger’s MyCode initiative, 3% have genetic variants that can be used to forecast health problems, and the number is expected to rise.
• Invitae research highlights utility of proactive genetic screening, importance of assessing secondary findings in genetic testing Healthy individuals are increasingly seeking genetic testing to identify their personal risks for inherited conditions that may affect disease emergence and outcome in areas such as such as cancer and cardiovascular disease. An analysis of 1,300 patients tested with a diagnostic-grade genetic screening panel designed for healthy adults found clinically actionable results in 16 percent of patients.
• Cancer Treatment Centers of America and Foundation Medicine Launch Joint Educational Campaign to Raise Consumer Awareness of Precision Medicine Approaches in Cancer Care The collaboration brings together CTCA, a nationwide cancer care network committed to delivering precision treatment, and Foundation Medicine, a leader in molecular testing that offers a suite of comprehensive genomic profiling (CGP) assays that may help identify alterations in an individual’s cancer and matches them with potentially relevant targeted therapies, including immunotherapies.

Strategic partnerships and collaborations

• Loxo Oncology and Illumina to partner on developing next-generation sequencing-based pan-cancer companion diagnostics Loxo Oncology will utilize a companion diagnostic version of TruSight Tumor 170 for Larotrectinib (NTRK) and LOXO-292 (RET).
• Charles River Laboratories and PathoQuest expand strategic biologics partnership The expansion of their strategic partnership agreement will provide next-generation sequencing (NGS) services to the biologics industry. As part of the expanded partnership, Charles River intends to make a direct investment in PathoQuest.

Product launches

• Launch of AMELIE (Automated Mendelian Literature Evaluation) – The Stanford Bejerano lab launched a new literature mining tool with intends to simplify monogenic disease diagnoses with exome sequencing. Gill Bejerano presented the findings from an analysis of more than 200 singleton Mendelian disease cases.
• Jude Cloud launches for researchers worldwide St. Jude, in collaboration with Microsoft and DNAnexus, will offer NGS data and analysis tools to accelerate research and cures for life-threatening pediatric diseases.
• Fluidigm releases CFTR next-generation sequencing library prep assay for use with the Juno System The new assay, the Advanta™ CFTR NGS Library Prep Assay, is a highly efficient and scalable next-generation sequencing (NGS) library prep workflow for sequencing of the CFTR (cystic fibrosis transmembrane conductance regulator) gene.
• Genoox collaborates with Bionano Genomics to enhance the detection of disease-causing structural variants in DNA The two companies intend to develop a genome informatics workflow to integrate and annotate Bionano structural variant calls with sequencing data within the Genoox platform.
• PerkinElmer collaborates with Helix to drive innovation in exome-based personal genomics The initial targeted product offering will return results for 59 genes that the American College of Medical Genetics and Genomics (ACMG) identifies as highly penetrant genetic conditions with established interventions aimed at significantly reducing morbidity and mortality. All DNA sequencing data for these products will be generated utilizing Helix’s proprietary Exome+ assay in its CLIA- and CAP-certified next-generation sequencing laboratory.
• Veracyte announces precision medicine collaboration with Loxo Oncology The agreement leverages Veracyte’s new Afirma Xpression Atlas Platform to advance development of highly selective medicines for patients with genetically defined cancers, including thyroid cancer.

Other

• TCGA Completes Comprehensive Genomic Analysis of 33 Cancer Types After a decade of analyzing over 11,000 tumors from 33 types of cancer, the collaboration between the National Cancer Institute and National Human Genome Research Institute has launched the Pan-Cancer Atlas, providing a comprehensive understanding of three focus areas: cell-of-origin patterns, oncogenic processes, and signaling pathways.
• FDA finalizes guidances to accelerate the development of reliable, beneficial next generation sequencing-based tests The new policies issued are meant to  provide a modern and flexible framework to generate data needed to support the FDA’s review of NGS-based tests, and give developers new tools to support the efficient development and validation of these technologies.
• Researchers Turn to Facebook to Survey Rare Disease Patients for Study Nara Sobreira (Assistant Professor of Pediatrics, Johns Hopkins University School of Medicine), described how she used the social media platform to contact patients with two rare diseases she has been studying — Ollier disease and Maffucci syndrome — to survey them for a study that also involved data from a review of the clinical literature.
• Paul R. Billings joins Natera as Chief Medical Officer and Senior Vice-President of Medical Affairs to help lead its efforts across reproductive health, oncology, and new emerging businesses.
• Chris Callahan joins PierianDx as Chief Commercial Officer to drive expansion of its genomics technology platform for clinical labs. Callahan previously was at Sunquest Information Systems where he held the role of VP and General Manager for GeneInsight.