Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Measures of albuminuria according to quintile of estimated dietary phosphorus density.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1c and estimated 24 h calorie-indexed dietary intakes of sodium, protein and saturated fat.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking, CRP, hemoglobin, calcium.</p><p>uAlb, urine albumin concentration; uCr, urine creatinine concentration; ACR, urine albumin:creatinine ratio; FE_alb, fractional excretion of albumin relative to creatinine.</p

Measures of albuminuria according to quintile of serum parathyroid hormone.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1c.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking status, CRP, hemoglobin, calcium, time of day of venepuncture,</p><p><b>model 4</b>: as model 3 but additionally adjusted for 25(OH)D quintile, season of measurement, loop diuretic and thiazide diuretic.</p><p>uAlb, urine albumin concentration; uCr, urine creatinine concentration; ACR, urine albumin:creatinine ratio; FE_alb, fractional excretion of albumin relative to creatinine.</p

Measures of albuminuria according to quintile of total alkaline phosphatase.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1c.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking, CRP, alanine transaminase, aspartate transaminase, hemoglobin, calcium, phosphorus.</p><p>uAlb, urine albumin concentration; uCr, urine creatinine concentration; ACR, urine albumin:creatinine ratio; FE_alb, fractional excretion of albumin relative to creatinine.</p

Characteristics of the US population represented by the NHANES 1999–2010, 2003–2006 and 1999–2004 cohorts.

<p>Data are given as mean (standard deviation) or median (interquartile range) for parametric and non-parametrically distributed variables respectively. N/A, not available.</p><p>SE, standard error; IQR, interquartile range.</p

Measures of albuminuria according to quintile of serum phosphorus.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1C.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking, CRP, hemoglobin, calcium, time of day of venepuncture.</p><p>uAlb, urine albumin concentration; uCr, urine creatinine concentration; ACR, urine albumin:creatinine ratio; FE_alb, fractional excretion of albumin relative to creatinine.</p

Measures of albuminuria according to quintile of bone-specific alkaline phosphatase.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1c.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking status, CRP, hemoglobin, calcium.</p

Measures of albuminuria according to quintile of serum 25(OH) vitamin D.

<p><b>model 1</b>: adjusted for age, gender and race.</p><p><b>model 2</b>: as model 1 but additionally adjusted for BMI, weight, waist circumference, systolic and diastolic blood pressures, total:HDL cholesterol ratio, eGFR, diabetes status, HbA1c.</p><p><b>model 3</b>: as model 2 but additionally adjusted for history of cardiovascular disease, poverty:income ratio, smoking status, 25(OH)vitamin D, CRP, hemoglobin, calcium and season of measurement.</p><p><b>model 4</b>: as model 3 but additionally adjusted for PTH quintile and time of day of venepuncture.</p><p>uAlb, urine albumin concentration; uCr, urine creatinine concentration; ACR, urine albumin:creatinine ratio; FE_alb, fractional excretion of albumin relative to creatinine.</p