The Tumor Fraction Estimated by Rapid On-Site Evaluation Is Useful for Assessing the Suitability of Biopsy Specimens for Multiplex Genetic Testing.

INTRODUCTION: Multiplex genetic testing (MGT) has become the mainstream method for genetic mutation testing in the field of lung cancer treatment, but the suitability criteria for MGT biopsy specimens are stringent. Although rapid on-site evaluation (ROSE) is considered a useful method for obtaining the suitable biopsy specimens for MGT, no direct comparisons of ROSE and MGT are available. In this study, we first evaluated the accuracy of MGT and ROSE in our hospital. Then, we explored the potential utility of the cytological findings of ROSE for indicating the adequacy of biopsy specimens for MGT. METHODS: These analyses were performed retrospectively using the data of 74 patients with lung cancer who underwent ROSE at our hospital in 2020-2022. RESULTS: Regarding the accuracy of MGT, the success rate was 97.9% and the frequency of epidermal growth factor receptor mutation in adenocarcinoma cases was 34.6%. The results of ROSE were then compared with histological diagnoses. The sensitivity and positive predictive value were 95.9% and 100.0%, respectively. To analyze the utility of the ROSE results for determining the adequacy of biopsy specimens for MGT, we determined the tumor fraction in the ROSE preparations (ROSE-T%) and the tumor fraction (B-T%)/tumor cell number (B-TN) in the biopsy specimens. When the threshold of the ROSE-T% was set at 80%, there were statistically significant biases of the B-T% ≥20%/B-TN ≥300 cases between the ROSE-T% ≥80% and <80% groups. CONCLUSION: This is the first report to suggest the utility of ROSE-T% in assessing the suitability of biopsy specimens for MGT. This predictive ability may add further value to ROSE and help reduce the time required for diagnostic testing, and thereby the patient burden.

Testing for Hereditary Predisposition in Patients with Gynecologic Cancers, Quo Vadis?

Genetic testing for a hereditary predisposition to gynecologic cancers has been available clinically since the 1990s. Since then, knowledge of the hereditary contribution to gynecologic cancers has dramatically increased, especially with respect to ovarian cancer. Although knowledge of the number of gynecologic cancer-predisposing genes has increased, the integration of genetic predisposition testing into routine clinical practice has been much slower. This article summarizes the technical and practical aspects of genetic testing in gynecologic cancers, the potential barriers to more widespread access and practice of genetic testing for hereditary predisposition to gynecologic cancers, and the potential solutions to these barriers.

CDH1 germ-line missense mutation identified by multigene sequencing in a family with no history of diffuse gastric cancer.

Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1 mutations were also detected in ILC with a frequency ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849G>A (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849G>A in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held.

Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory.

Next-generation sequencing enables testing for multiple genes simultaneously ('panel-based testing') as opposed to sequential testing for one inherited condition at a time ('syndrome-based testing'). This study presents results from patients who underwent hereditary colorectal cancer (CRC) panel-based testing ('ColoNext(™) '). De-identified data from a clinical testing laboratory were used to calculate (1) frequencies for patient demographic, clinical, and family history variables and (2) rates of pathogenic mutations and variants of uncertain significance (VUS). The proportion of individuals with a pathogenic mutation who met national syndrome-based testing criteria was also determined. Of 586 patients, a pathogenic mutation was identified in 10.4%, while 20.1% had at least one VUS. After removing eight patients with CHEK2 mutations and 11 MUTYH heterozygotes, the percentage of patients with 'actionable' mutations that would clearly alter cancer screening recommendations per national guidelines decreased to 7.2%. Of 42 patients with an 'actionable' result, 30 (71%) clearly met established syndrome-based testing guidelines. This descriptive study is among the first to report on a large clinical series of patients undergoing panel-based testing for inherited CRC. Results are discussed in the context of benefits and concerns that have been raised about panel-based testing implementation.