Founder BRCA1 mutations in Nepalese population.

BACKGROUND: Founder mutation is a heritable genetic alteration observed with high frequency in a geographically and culturally isolated population where one or more ancestors becomes the forebearer of the altered gene. The current study reports two founder mutations in the BRCA1 gene in the Nepalese people. METHODS: Germline BRCA testing in all surface epithelial ovarian cancers and the selected case of breast, prostate, and pancreatic cancers has been the standard practice from 2016 to 2021. One thousand one hundred thirtythree probands were screened for germline BRCA variants by next generation sequencing. The variants were classified as per the American Society of Medical Genetics and Genomics recommendations. Pathogenic (class V) and likely pathogenic (class IV) were considered clinically relevant and utilized for cascade screening. RESULTS: Nepalese population made up a subcohort of 5.12% (58/1,133) of probands tested for germline BRCA1/2 variants. Twenty-seven of these 58 tested harbored pathogenic genetic alterations in BRCA1/2 genes, with 23 being BRCA1 mutant. Sixteen of 23 BRCA1 mutant cases shared one common pathogenic mutation c.2214_2215insT (p.Lys739Ter) (NM_007294.4). Additionally, a second highly recurrent mutation in BRCA1 gene c.5068A>T (p.Lys1690Ter) (NM_007294.4) was noted in six patients from this population. CONCLUSIONS: The overwhelming abundance of the above two variants in a geographically confined population confers these two genetic alterations a status of founder mutations amongst the people of Nepal. A more extensive population-based study to reaffirm these findings will help establish a dual site-specific germline testing similar to the "Multisite-3-assay" in Ashkenazi Jews as the primary screening tool, especially in a resource-constrained environment.

Machine learning-based algorithm demonstrates differences in del19 and L858R EGFR subgroups in non-small cell lung cancer: a single center experience.

BACKGROUND: Exon del19 and L858R mutations account for 90% of EGFR mutant non-small cell lung cancer (NSCLC). LUX lung 3 and 6 initially reported a survival difference between these two. However, other studies did not demonstrate the same. By using machine learning (ML), it is possible to discover novel patterns for cancer susceptibility, recurrence, prognostication, and therapy. We evaluate the effect of these two molecular subtypes on overall survival/progression-free survival (OS/PFS). METHODS: 413 patients with stage IV EGFR mutant NSCLC were analyzed for clinicopathologic features, treatment details, and survival outcome. PFS prediction models were built using ensemble decision trees, and random forest. Ensemble decision trees were built and validation was performed using survival analysis. Clustering regression techniques were then applied to train and test the prediction of the 1st PFS of patients. RESULTS: The median age of the cohort was 59 years comprising 53% males and 47% females. 275 (66.5%) patients showed a del19 mutation type and 138 (33.5%) harbored L858R. After clustering, the most important variables were age (P<0.05), ECOG performance status (PS) (P<0.04), PDL1 (P<0.09), smoking status (P<0.01) and to a lesser extent, number of extrathoracic metastasis (ETM) sites (median 1.2, P<0.06), brain metastasis (P<0.06) and gender (P<0.08). The prediction for 1st PFS for del19 showed mean absolute error of 2.6 months and 4.72 months for L858R. The accuracy was 79.8% with 82% sensitivity, 79% specificity and AUC: 0.72. The precision was 92% with a Mathews correlation coefficient of 0.59. CONCLUSION: This study used machine learning modeling with fair accuracy to demonstrate that ECOG PS, age at diagnosis, and smoking status are the three main predictive factors of PFS in these patients.

EGFR detection by liquid biopsy: ripe for clinical usage.

Introduction: With the International Association for the Study of Lung Cancer (IASLC) recommendations promoting liquid biopsy as a primary detection tool, a new era of research has begun. The authors aimed to study the concordance of plasma genotyping platforms against the tissue gold standard. Methods: 184 patients with non-small cell lung cancer underwent EGFR genotyping using Cobas, droplet digital polymerase chain reaction (ddPCR) and Therascreen assays from 2019-2020. Results: Of 184 cases, 70 were positive by Cobas, 51 by ddPCR and 69 by Therascreen. The sensitivity of Cobas was 97.1% and the sensitivity of ddPCR was 71%. Receiver operating characteristic analysis showed an area under the curve of 0.977 for Cobas and 0.846 for ddPCR. Conclusion: In line with the FLAURA trial of osimertinib making its way to first-line and given the IASLC recommendations, it is important to understand the attributes of these tests to initiate appropriate treatment.

Lay abstract Lung cancer is one of the most common malignancies and has been known to have a dismal outcome. However, owing to evolution in the knowledge of disease biology and processes, many molecules have been discovered that can be used in targeted therapy. To institute this modality of treatment, detection of alterations in these specific molecules, namely: EGFR, ALK, ROS1, RET, MET, KRAS G12C, BRAF V600E, NTRK1, NTRK2, NTRK3 and ERBB2 is necessary. This has traditionally been done using single-gene assays, which require more tissue. This is a major limitation in cases of non-small cell lung carcinoma, as the biopsies are small. Hence, new technologies like next-generation sequencing have emerged that offer a one-stop solution for these cases. In cases where tissue is very scant, the use of peripheral blood has now been recommended by international guidelines for primary detection of these molecular alterations. This article describes the concordance of tissue-based detection and blood-based detection using three different assays, for the detection of EGFR alterations. Although promising results were obtained largely for blood-based assays, liquid and tissue biopsies are complementary.

T-ALL Minimal Residual Disease Using a Simplified Gating Strategy and Its Clinico-hematologic Correlation: A Single Center Experience from North India.

The presence of minimal residual disease (MRD) is one of the strong predictors of disease outcome in various hematological malignancies including B-ALL and T-ALL, independent of pre-therapeutic risk factors. There is scant Indian data on MRD by flowcytometry in T-ALL including gating strategies, clinical correlation etc. The primary aim of this retrospective observational study was to define the clinico-hematologic characteristics and prognostic significance of patients with ETP/near-ETP versus non-ETP immunophenotype, especially in terms of minimal residual disease at different time points as well as event-free survival (1 year). Baseline hematologic characteristics along with post-induction (Day-35) and post-consolidation (Day-78) MRD in bone marrow samples from newly diagnosed T-ALL patients were studied. 14.3% patients had ETP-ALL immunophenotype, 11.4% were near-ETP ALL patients and the remaining 74.5% were of non-ETP subtype. The ETP/near ETP patients was significantly associated with higher risk of MRD positivity ( > 0.01%) at the end of induction in comparison to the non-ETP patients (p = 0.033). Also, these patients showed a trend towards proclivity to anemia (p = 0.06) and higher rates of induction failure (p = 0.07) However, no difference was observed between the two subgroups in terms of age, high TLC, thrombocytopenia, adverse cytogenetics, steroid responsiveness on Day + 8 of induction, MRD-positivity > 0.01% at the end of consolidation and EFS-1 year. Through this preliminary study, it can be stated clearly that ETP status is associated with MRD > 0.01% post-induction but has no significant impact on long-term survival of these patients.