7.2 Genetics and Genomics

Genetics on CPHON is not a recitation of every fusion ever published. TCO II.A.3 asks whether you can tell a somatic tumor finding from a germline predisposition, when to pick up the phone for genetic counseling, why mercaptopurine can flatten a child's counts if TPMT or NUDT15 is deficient, and how cytogenetics, FISH, and sequencing change risk and add a targeted drug. The named rearrangements—MYCN, BCR-ABL1, PML-RARA, EWSR1, FOXO1—already appear in disease chapters. Here you learn the how, not a new laundry list.

Somatic versus germline

A somatic mutation or fusion lives in the tumor (or the leukemic clone). It is not in the child's egg or sperm cells and is not passed to future children. BCR-ABL1 in Ph-positive ALL is a somatic leukemia finding. EWSR1-FLI1 in Ewing sarcoma is a somatic diagnostic fusion. A germline variant is present in essentially every cell, including the germline, and can be inherited or arise de novo. Germline variants explain cancer predisposition syndromes, sibling risk, and sometimes a different surveillance or radiation plan. The same gene can appear in both stories: a somatic TP53 mutation in a tumor is not automatically Li-Fraumeni syndrome; germline TP53 testing is a separate question with family implications.

Teach families the difference in one sentence. This result tells us how to treat this cancer, versus this result tells us whether your child's body was born with a higher cancer risk and whether relatives need counseling. Mixing those sentences is how a parent hears that every sibling must start chemotherapy.

Predisposition syndromes you should be able to flag

You are not the geneticist. You are the nurse who notices bilateral disease, an odd age, an associated anomaly, or a family history and does not let the consult wait until after maintenance.

• Li-Fraumeni syndrome (TP53): sarcomas, osteosarcoma, CNS tumors, adrenocortical carcinoma, and early-onset breast cancer in the family. Avoid unnecessary radiation when an effective alternative exists; the child and relatives need formal counseling.
• Heritable retinoblastoma (RB1): bilateral or multifocal disease is germline until proven otherwise, even with a negative family history, because many RB1 variants are de novo. Later osteosarcoma and soft-tissue sarcoma risk belongs in survivorship teaching.
• WT1-related and overgrowth renal risk: WAGR (Wilms tumor, aniridia, genitourinary anomalies, range of developmental delay), Denys-Drash, and Beckwith-Wiedemann syndrome (BWS) change screening—serial abdominal ultrasound, and AFP as the hepatoblastoma program specifies for BWS—not a wait-for-a-visible-mass plan. BWS is an imprinting/overgrowth syndrome (11p15), not a WT1 deletion; the shared nursing action is still ultrasound screening.
• Neurofibromatosis type 1 (NF1): café-au-lait macules, optic pathway glioma, later malignant peripheral nerve-sheath tumor. Vision checks are not optional trivia.
• Down syndrome (trisomy 21): transient abnormal myelopoiesis (TAM) in neonates; later ALL and myeloid leukemia of Down syndrome. Not every neonate with blasts is transplanted on day 2; not every toddler with Down syndrome and cytopenias has a virus.
• Fanconi anemia: marrow failure, AML, and solid tumors, plus marked sensitivity to DNA-crosslinking chemotherapy. Dose modification is a protocol decision; full unmodified alkylator intensity is not a nursing improvisation.
• DICER1 syndrome: pleuropulmonary blastoma, ovarian Sertoli-Leydig tumor, multinodular goiter, cystic nephroma. A young child with a lung cyst plus a family thyroid story is not just a pneumonia cavity.
• Rhabdoid tumor predisposition (SMARCB1): atypical teratoid/rhabdoid tumor and renal rhabdoid disease in very young children. Brain imaging belongs in the renal-rhabdoid workup.

When to refer genetic counseling

Refer when disease is bilateral or multifocal, occurs at an unusual age, comes with congenital anomalies, or sits in a family history of early, multiple, or rare cancers. A 14-month-old with bilateral retinoblastoma does not wait for three generations of pedigrees. A 3-year-old with Wilms tumor and aniridia already has a counseling indication. A teenager with osteosarcoma and a parent who died of a brain tumor at 31 is Li-Fraumeni until counseling says otherwise. Document the referral. Do not promise a negative test as a cure.

Pharmacogenomics: TPMT, NUDT15, and thiopurines

Mercaptopurine (6-MP) and thioguanine are backbone thiopurines in ALL maintenance and some AML pathways. TPMT and NUDT15 enzymes help inactivate thiopurine metabolites. Children with deficient activity accumulate active thioguanine nucleotides in marrow and can develop life-threatening myelosuppression at usual milligram-per-square-meter doses. Protocols use genotype or activity to guide dose reductions. Do not memorize a star-allele table as an ONCC fact; allele nomenclature changes and is not the scored point. The scored point is: unexplained, profound neutropenia or pancytopenia after mercaptopurine is a pharmacogenomic emergency, not nonadherence until proven guilty, and you do not restart full-dose 6-MP because the child looks well today.

A 5-year-old in ALL maintenance whose ANC crashes after the first weeks of mercaptopurine needs a hold, an infection workup, and a TPMT/NUDT15 pathway review with the protocol team—not a lecture about hiding pills. Conversely, a child with known deficiency still receives thiopurines on many protocols, just at a reduced, protocol-specified dose. Deficiency is not a reason to invent a homemade regimen.

How cytogenetics, FISH, and NGS change risk and therapy

Karyotype (conventional cytogenetics) sees chromosome number and many large rearrangements; it takes days. FISH uses a fluorescent probe for a known target (BCR-ABL1, KMT2A, EWSR1, PML-RARA) and returns faster. NGS panels and RNA fusion assays find cryptic fusions and mutations karyotype can miss. None of these replace morphology and flow on day 0, and none return in an hour.

Teach how the result is used, using names families already hear in disease chapters:

• BCR-ABL1 (Philadelphia chromosome) in ALL does not change the fact that this is ALL; it adds a tyrosine kinase inhibitor (TKI) such as imatinib (or another protocol TKI) to the backbone and changes risk assignment.
• PML-RARA defines APL and redirects therapy to tretinoin and arsenic trioxide because coagulopathy, not an asparaginase induction, is the emergency.
• MYCN amplification in neuroblastoma is a biologic risk factor that helps place the child in a high-risk group; it is not a bedside vital sign.
• EWSR1 rearrangement confirms Ewing family sarcoma when morphology is a small-round-blue-cell tumor; it is why Ewing is not osteosarcoma in a younger child.
• FOXO1 fusion in rhabdomyosarcoma supports alveolar biology and a higher-risk conversation; fusion-negative disease is often closer to embryonal risk.

Initial chemotherapy starts on clinical diagnosis. Genetics then refine intensity and add targeted agents. That is why families hear that treatment started while cytogenetics are still pending.

Confidentiality, assent, and consent for genetic testing in minors

Somatic tumor testing is part of cancer diagnosis; explain it as disease characterization. Germline testing is different. A parent or legal guardian gives permission. A developmentally able child or adolescent gives assent. You do not coerce a 16-year-old into a predisposition panel by saying the port will be pulled if they refuse. Results may reveal misattributed parentage, unexpected carrier status, or a parent's own cancer risk. Share results along the agreed family plan, in private, and do not post genotypes on the hallway whiteboard. Siblings are not automatically tested without their own consent process. A 12-year-old can understand that one test looks at the cancer cells and another looks at the genes they were born with and might tell us about brothers or sisters. Keep those conversations separate.

The CPHON product is a nurse who flags bilateral disease, holds mercaptopurine when a deficient metabolizer is crashing, explains why imatinib appears on a Ph-positive ALL roadmap, and never treats a germline report as hallway gossip.