A 7-year-old boy presents with pallor, petechiae, and bone pain. Bone marrow examination reveals acute lymphoblastic leukemia. Karyotyping shows a modal chromosome number of 38. The cytogenetic abnormality marked **B** in the diagram is identified. Which of the following genetic alterations is MOST strongly associated with this cytogenetic subgroup and warrants immediate screening for an underlying familial cancer syndrome?
A. BCR-ABL1 fusion (Philadelphia chromosome)
B. TP53 mutations (often germline, raising concern for Li-Fraumeni syndrome)
C. RAS pathway mutations (NF1, NRAS, KRAS) with IKZF3 alterations
D. t(12;21) ETV6-RUNX1 translocation
Explanation
Why TP53 mutations (often germline, raising concern for Li-Fraumeni syndrome) is right
The structure marked B represents hypodiploidy (<44 chromosomes). When the modal chromosome count is 38, this falls into the LOW HYPODIPLOID subgroup (32–39 chromosomes), which is STRONGLY ASSOCIATED with TP53 mutations — often germline alterations indicating Li-Fraumeni syndrome. According to Robbins Pathology 11e and WHO Classification 5e, low hypodiploid ALL patients with TP53 mutations require screening for familial cancer predisposition, making this the most clinically critical association for this cytogenetic subgroup.
Why each distractor is wrong
RAS pathway mutations (NF1, NRAS, KRAS) with IKZF3 alterations: These are characteristic of NEAR-HAPLOID ALL (24–31 chromosomes), not low hypodiploid ALL (32–39 chromosomes). The chromosome count of 38 places this case in the low hypodiploid category.
t(12;21) ETV6-RUNX1 translocation: This is a favorable-risk cytogenetic abnormality in B-ALL, typically associated with hyperdiploidy or normal karyotype, not hypodiploidy. It is marked as C in the diagram and is unrelated to the hypodiploid subgroup.
BCR-ABL1 fusion (Philadelphia chromosome): This is the hallmark of chronic myeloid leukemia and Philadelphia chromosome-positive ALL, which is a distinct entity from hypodiploid ALL and carries different prognostic and therapeutic implications.
High-YieldNEET PG
Low hypodiploid ALL (32–39 chromosomes) + TP53 mutation = screen for Li-Fraumeni syndrome; near-haploid ALL (24–31 chromosomes) = RAS pathway mutations.
Robbins Pathology 11e; Hoffman Hematology 8e; WHO Classification 5e
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