bims-lifras 2023-11-19 papers

ESMO Open. 2023 Nov 09. pii: S2059-7029(23)01292-9. [Epub ahead of print]8(6): 102051

Sequencing paired tumor DNA and white blood cells improves circulating tumor DNA tracking and detects pathogenic germline variants in localized colon cancer.

F Gimeno-Valiente, J Martín-Arana, R Tébar-Martínez, V Gambardella, C Martínez-Ciarpaglini, B García-Micó, B Martínez-Castedo, B Palomar, M García-Bartolomé, V Seguí, M Huerta, D Moro-Valdezate, V Pla-Martí, L Pérez-Santiago, S Roselló, D Roda, A Cervantes, N Tarazona.

BACKGROUND: In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting a higher risk of recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study, we assess the potential value of adding white blood cells (WBCs) to tumor tissue sequencing to enhance the accuracy of sequencing results.
PATIENTS AND METHODS: A total of 148 patients diagnosed with localized CC were prospectively recruited at the Hospital Clínico Universitario in Valencia (Spain). Employing a custom 29-gene panel, sequencing was conducted on tumor tissue, plasma and corresponding WBCs. Droplet digital PCR and amplicon-based NGS were performed on plasma samples post-surgery to track MRD. Oncogenic somatic variants were identified by annotating with COSMIC, OncoKB and an internal repository of pathogenic mutations database. A variant prioritization analysis, mainly characterized by the match of oncogenic mutations with the evidence levels defined in OncoKB, was carried out to select specific targeted therapies.
RESULTS: Utilizing paired tumor and WBCs sequencing, we identified somatic mutations in all patients (100%) within our cohort, compared to 89% using only tumor tissue. Consequently, the top 10 most frequently mutated genes for plasma monitoring were altered. The sequencing of WBCs identified 9% of patients with pathogenic mutations in the germline, with APC and TP53 being the most frequently mutated genes. Additionally, mutations in genes related to clonal hematopoiesis of indeterminate potential were detected in 27% of the cohort, with TP53, KRAS, and KMT2C being the most frequently altered genes. There were no observed differences in the sensitivity of monitoring MRD using ddPCR or amplicon-based NGS (p = 1). Ultimately, 41% of the patients harbored potentially targetable alterations at diagnosis.
CONCLUSION: The germline testing method not only enhanced sequencing results and raised the proportion of patients eligible for plasma monitoring, but also uncovered the existence of pathogenic germline variations, thereby aiding in the identification of patients at a higher risk of hereditary cancer syndromes.

Keywords: circulating tumor DNA; colon cancer; germline variants; minimal residual disease; precision medicine

DOI: https://doi.org/10.1016/j.esmoop.2023.102051

Semin Diagn Pathol. 2023 Nov 10. pii: S0740-2570(23)00098-9. [Epub ahead of print]

Diagnostic work-up of hematological malignancies with underlying germline predisposition disorders (GPD).

Rashmi Kanagal-Shamanna, Kristian T Schafernak, Katherine R Calvo.

Hematological malignancies with underlying germline predisposition disorders have been recognized by the World Health Organization 5th edition and International Consensus Classification (ICC) classification systems. The list of genes and the associated phenotypes are expanding and involve both pediatric and adult populations. While the clinical presentation and underlying molecular pathogenesis are relatively well described, the knowledge regarding the bone marrow morphologic features, the landscape of somatic aberrations associated with progression to hematological malignancies is limited. These pose challenges in the diagnosis of low-grade myelodysplastic syndrome (MDS) to hematopathologists which carries direct implication for various aspects of clinical management of the patient, donor selection for transplantation, and family members. Here in, we provide a focused review on the diagnostic work-up of hematological malignancies with underlying germline predisposition disorders with emphasis on the spectrum of hematological malignancies associated with each entity, and characteristic bone marrow morphologic, somatic cytogenetic and molecular alterations at the time of diagnosis of hematological malignancies. We also review the key clinical, morphologic, and molecular features, that should initiate screening for these entities.

Keywords: AML; DDX41; GATA2; Germline predisposition to myeloid malignancy; MDS; RUNX1

DOI: https://doi.org/10.1053/j.semdp.2023.11.004

Front Oncol. 2023 ;13 1253867

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer.

Safiye Yildiz, Takudzwa N Musarurwa, Ursula Algar, Ramadhani Chambuso, George Rebello, Paul A Goldberg, Raj Ramesar.

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.
Materials and methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.
Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.
Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

Keywords: South African populations; early-onset colorectal cancer; genetic insight; germline variants; hereditary colorectal cancer (CRC); indigenous african cohort; multigene panel; next generation sequencing -(NGS)

DOI: https://doi.org/10.3389/fonc.2023.1253867