Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, chair of pathology, Oregon Health and Science University, Portland; Richard D. Press, MD, PhD, professor and director of molecular pathology, OHSU; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Andrés G. Madrigal, MD, PhD, assistant professor, clinical, Ohio State University Wexner Medical Center, Columbus; and Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh.

Genetic testing for people with spontaneous coronary artery dissection

November 2022—Spontaneous coronary artery dissection is an uncommon cause of acute heart attack. It is not associated with high cholesterol or atherosclerosis but, instead, occurs when a small tear or separation in the wall of the coronary artery leads to blood entering a false lumen, occluding blood flow and impairing oxygenation of the heart muscle. The condition is most often seen in young women, and it is thought to have a number of underlying etiologies and risk factors. Some cases of spontaneous coronary artery dissection (SCAD) are thought to have a monogenic etiology caused by pathogenic alterations in genes associated with connective tissue diseases, such as Ehlers-Danlos syndrome, Marfan syndrome, and Loeys-Dietz syndrome, as well as fibrillar collagen disorders. Other cases are likely polygenic or may be associated with a systemic vascular disease, such as fibromuscular dysplasia. To learn more about the underlying genetic causes of the condition, the authors performed whole exome sequencing on a cohort of 94 patients with high-risk SCAD. They first focused on 19 genes known to be associated with vascular connective tissue disorders and three genes identified in previous genomewide-association studies and known to be associated with increased risk of SCAD. Variants in the aforementioned genes were seen in 16 (17 percent) of the patients with high-risk SCAD, and they were significantly enriched in the SCAD cohort compared to population databases. The most commonly altered gene was COL3A1 (seen in four people). Other alterations included variants in genes associated with Loeys-Dietz syndrome (four people) and genes previously identified in genomewide-association studies (six people). Using the 2020 Association for Clinical Genomic Science and American College of Medical Genetics and Genomics criteria, the authors classified four of the variants as pathogenic or likely pathogenic. Although the remaining variants identified in the study were classified as being of undetermined significance, there was often limited evidence of pathogenicity because the variants had not been previously studied or were not part of the ClinVar database (a free, public archive of human genetic variants and interpretations of their significance to disease). For example, although one alteration in the COL3A1 gene affected the canonical exon 3 splice site and was predicted to result in aberrant splicing, it was classified as a variant of undetermined significance because it is not known how loss of this exon affects protein function. In a clinical setting, it may be necessary to collect additional patient history and conduct workups of patients’ family members to better understand these variants. Moreover, the number of variants of uncertain significance identified in this study emphasizes the importance of conducting functional studies to characterize the biological effects of these variants. Overall, this study highlights the underlying genetic causes of SCAD. Therefore, genetic testing should be considered for people presenting with this condition.

Wang Y, Starovoytov A, Murad AM, et al. Burden of rare genetic variants in spontaneous coronary artery dissection with high-risk features. JAMA Cardiol. 2022. doi:10.1001/jamacardio.2022.2970

Correspondence: Dr. Santhi K. Ganesh at sganesh@umich.edu or Dr. Jacqueline Saw at jsaw@mail.ubc.ca

Clinical utility of genomic testing in metastatic breast cancer

Precision medicine in oncology is rapidly becoming a standard of care. Next-generation sequencing assays increasingly are being used to identify mutations in oncogenes and tumor-suppressor genes that could potentially impact cancer treatment decisions. Targeted therapies or clinical trials are available for some alterations, but clinicians typically are unsure of how to address the others. Several tiered systems have been developed to classify variants identified using clinical assays and to highlight those with strong or potential clinical significance. Among them are the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists (AMP/ASCO/CAP) tiered system, European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) classification system, and OncoKB system, developed by Memorial Sloan Kettering Cancer Center. While they have varying characteristics, all share the goal of providing information to patients and oncologists about which genomic variants are most likely to impact clinical outcomes. The authors examined the clinical utility of genomic testing and targeted therapy in metastatic breast cancer patients and highlighted the importance of using tiers to classify variants. They included multiple genomic assays and methodologies in their study so the results are broadly applicable to molecular testing in general. The authors assessed how precision medicine results were used in a cohort of 238 patients with HER2-negative metastatic breast cancer. The patients had undergone comprehensive tumor profiling and were enrolled in clinical trials in which they were randomized between maintenance chemotherapy and targeted therapy matched to genomic alteration. Among the 115 patients who had alterations within the most clinically important tiers (ESCAT tier one [the drug matched to the genomic alteration has been proven to be effective] or tier two [the drug matched to the genomic alteration has been associated with preliminary evidence of efficacy]), progression-free survival was significantly longer for those receiving targeted therapy than for those on maintenance chemotherapy (9.1 months versus 2.8 months, respectively). The ESCAT tier one and two alterations detected by the assays used in the study included alterations in BRCA1/2, PALB2, PIK3CA, AKT1, PTEN, and ERBB2. In the total cohort of 238 patients, the difference in progression-free survival outcome between those receiving targeted therapy and those receiving maintenance chemotherapy was not statistically significant. This was largely because there was essentially no survival benefit for patients with alterations below ESCAT tier two who received targeted therapy. Subgroup analysis showed that a majority of the survival benefit was seen in patients with germline BRCA1 and BRCA2 mutations who received the targeted therapy olaparib. Although the study results suggest that lower tier mutations might not be clinically relevant, the tiers of specific mutations may change as the medical community learns more about cancer and develops new targeted treatments and clinical trials. Therefore, it is important that those practicing molecular pathology stay up to date with advances in precision medicine to achieve optimal patient survival outcomes.