Notes on Genetic Diagnosis

Genetic testing is indispensable for hematological disease management. For acute leukemia, it supports diagnosis, prognosis assessment and treatment guidance. However, interpreting genetic mutation reports is highly complex. Clinicians must distinguish germline (inherited) mutations from somatic tumor-derived variants, clarify whether germline variants contribute to leukemia susceptibility, analyze mutation loci, variant combinations, and their impacts on prognosis and targeted drug options. Joint discussion between clinicians and molecular genetics specialists is required to formulate rational treatment plans.

Today, Zheng Qinlong, Director of our Molecular Diagnostics Laboratory from Beijing GoBroad Boren Hospital, co-analyzed a patient’s genetic report with clinical physicians, bringing profound insights to all attendees. Misinterpretation of mutations may delay treatment or lead to inappropriate regimens.

Clinical Case 1

One AML patient carried double CEBPA and CSF3R mutations and achieved complete remission after one chemotherapy cycle. Another hospital misclassified the case as favorable-risk AML solely based on double CEBPA mutations and administered repeated chemotherapy. The patient relapsed after six cycles.

Upon admission to our hospital, molecular analysis confirmed the double CEBPA variants were germline susceptibility mutations rather than somatic leukemia mutations. Germline double CEBPA raises leukemia risk and predisposes patients to new secondary mutations and relapse after chemotherapy; the CSF3R Q754X mutation correlates with poor prognosis. We recommended allogeneic hematopoietic stem cell transplantation immediately after remission to avoid recurrent disease and organ damage from prolonged chemotherapy.

Clinical Case 2

A 46-year-old female newly diagnosed with AML attained partial remission after one cycle of chemotherapy. A 127-gene panel detected somatic IDH2, NPM1 and BRAF mutations, plus suspected germline DNMT3A and ATRX variants.

While IDH2+NPM1 mutations generally confer favorable prognosis, concurrent BRAF mutation predicts inferior outcomes. Yet BRAF alterations respond to Trametinib and Vemurafenib, and combination therapy can boost efficacy. Nail DNA testing was ordered to verify whether DNMT3A is germline. Our comprehensive proposal: chemotherapy combined with BRAF-targeted therapy to achieve complete remission, followed by allogeneic hematopoietic stem cell transplantation. Two germline susceptibility genes were identified via panel sequencing, suggesting an unrelated donor or expanded susceptibility gene screening for matched related donor selection.

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