The MEN1 age-penetrance curve: 7% by age 10, 52% by 20, 87% by 30
also called MEN1 penetrance by decade · MEN1 age of onset curve
In families carrying a broken menin gene, disease appears slowly: about 7 in 100 carriers have it by their tenth birthday, half by twenty, and nearly all by forty. That slow build-up is the best available yardstick for how long menin has to be missing before something goes wrong.
The same thing, for a scientist
From 63 unrelated MEN1 kindreds comprising 195 affected and 396 unaffected members, 201 MEN1 mutant-gene carriers (155 affected, 46 unaffected) were identified, and age-related penetrance of MEN1 was defined as 7%, 52%, 87%, 98%, 99% and 100% at 10, 20, 30, 40, 50 and 60 years of age respectively [E1]. An independent French series of 220 carriers put penetrance above 95% by age 30 [E2]. This curve is the quantitative anchor for the whole menin-inhibitor endocrine question, because it says what lifelong germline haploinsufficiency buys you per unit time: roughly 0.7 percentage points of disease per year in the first decade, rising steeply through the second.
The curve, and what it is a curve of1 deeper
| Age (years) | Cumulative penetrance |
|---|---|
| 10 | 7% |
| 20 | 52% |
| 30 | 87% |
| 40 | 98% |
| 50 | 99% |
| 60 | 100% |
Source: 201 identified MEN1 mutant-gene carriers from 63 kindreds 1.
Two things this curve is not:
- It is not a curve of tumour initiation. It is a curve of clinical or biochemical ascertainment in families under surveillance, so it mixes detection intensity into the biology.
- It is not a dose-response curve for menin. Every person on it has had exactly one functional MEN1 allele in every cell since conception. It tells you what 50% germline gene dosage produces over decades; it does not tell you what, say, 60% pocket occupancy for four months produces.
How to use it for the drug question, honestly
The right use is as an upper bound on plausible speed. A carrier has half the menin gene dose in every endocrine cell, permanently, from conception - and still has a 93% chance of being disease-free at age 10 1. A child receiving revumenib is exposed for a median of 2.5 months on the pivotal safety population, with 10% exposed beyond 6 months, and the exposure is reversible.
If permanent 50% loss for 3,650 days yields 7% disease, then partial reversible disruption for ~75 days is, on this arithmetic alone, a small risk. That is the strongest available argument against the late-effects hypothesis, and it should be stated first.
The arguments that survive it are narrower and should be kept narrow:
- A pocket ligand at therapeutic exposure may disrupt more than 50% of menin's pocket-mediated function, so the germline carrier is not the right comparator for magnitude.
- Some children will be on drug for far longer than 2.5 months - post-transplant maintenance in AUGMENT-101 ran to 199 days at data cut-off, and the FDA postmarketing requirement specifies at least 3 years of treatment for the patients it enrols.
- The curve describes tumours. Functional endocrine perturbation - a raised PTH, a slowed growth velocity - is a different and faster endpoint, and is what the revumenib label already reports.
| metric | cumulative age-related penetrance |
|---|---|
| unit | percent of germline MEN1 mutation carriers affected |
| population | MEN1 germline mutation carriers from 63 kindreds |
| region | United Kingdom |
| year | 1998 |
| source | Bassett et al., Am J Hum Genet 62:232-44 (PMID 9463336) |
| n carriers | 201 |
| n kindreds | 63 |
| comparator exposure | median revumenib exposure 2.5 months (range <1 to 40 months); 10% exposed beyond 6 months |
curve
[
{
"age_years": 10,
"penetrance_pct": 7
},
{
"age_years": 20,
"penetrance_pct": 52
},
{
"age_years": 30,
"penetrance_pct": 87
},
{
"age_years": 40,
"penetrance_pct": 98
},
{
"age_years": 50,
"penetrance_pct": 99
},
{
"age_years": 60,
"penetrance_pct": 100
}
]- This curve is the strongest single argument against the menin-inhibitor endocrine hypothesis and must be presented as such: permanent 50% menin loss from conception still leaves 93% of carriers disease-free at 10.
- Using a germline-carrier curve to bound a drug exposure assumes the perturbations are commensurable, and they are not: gene dosage and pocket occupancy differ in magnitude, reversibility and which menin functions they touch.
- The curve measures tumours. If menin inhibition has an endocrine effect in children it will show up first as a laboratory number, not a lesion, and this curve is silent about that.
- What is the penetrance below age 5? Every cohort reports a first bin at 10 years, and the youngest ages are exactly the ones that matter for a drug approved from age 1.
- How much of the curve's early flatness is biology and how much is that nobody was checking calcium in 8-year-olds in the 1990s? Re-deriving the curve from a modern cohort with protocolised annual screening from age 5 would separate these.
- What is the functional, non-tumour penetrance - the fraction of carriers with a biochemical abnormality but no lesion - by age? That is the endpoint a drug exposure would move first, and no cohort reports it.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Analysis of 63 unrelated MEN1 kindreds (195 affected and 396 unaffected members) identified 201 MEN1 mutant-gene carriers and defined the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99% and 100% at 10, 20, 30, 40, 50 and 60 years of age respectively.
Characterization of mutations in patients with multiple endocrine neoplasia type 1 · Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV · Am J Hum Genet 62:232-44 1998What this evidence cannot show
Read as abstract. Penetrance in kindreds ascertained through affected probands, which biases upward, and reported without confidence intervals. Detection depends on the intensity of family screening in the 1990s, so the true biological onset is earlier than the ascertained onset by an unknown amount. The endpoint is any MEN1 manifestation, not any specific tumour.
Evidence that argues against this (1)
- A later multicentre study of 258 carriers found tumour penetrance so heterogeneous - earliest manifestation ranging from 9 to 25 years and latest from 68 to 77 years depending on tumour type, and not predictable from mutation type - that the authors concluded individual penetrance cannot be predicted. A single smooth population curve therefore conceals a wide individual spread and should not be used to reason about any one patient. Machens A et al. 2007
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In an independent French series, 220 MEN1 gene carriers (167 affected, 53 unaffected) were identified across 84 families and isolated cases, and age-related penetrance was estimated at greater than 95% at age over 30 years, with no genotype-phenotype correlation found.
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. · Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, et al., Calender A · Am J Hum Genet 63:455-67 1998What this evidence cannot show
Read as abstract. Consistent with the Bassett curve at age 30 (87% there, >95% here); the difference is plausibly ascertainment and definition rather than biology. Family-based ascertainment again biases upward.
Evidence that argues against this (1)
- Both series ascertain through identified mutation carriers in families, so both are subject to the same enrichment for penetrant kindreds. Agreement between them bounds sampling error, not ascertainment bias, and the curve they agree on is the carrier curve. American Journal of Human Genetics 1998
- related to →Primary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin
the syndrome-level curve whose earliest events are overwhelmingly parathyroid
- refutes →The same pocket suppresses JUND: menin inhibition's unmeasured endocrine liability in infants
permanent 50% germline menin loss still leaves 93% of carriers disease-free at age 10 - the strongest argument against the hypothesis
what lifelong MEN1 haploinsufficiency produces per unit time
- ← depends onHow long does menin have to be gone? Two months in a mouse islet, a decade or more in a human carrier
the human anchor: 7% at age 10 with permanent germline haploinsufficiency
Class 3: the penetrance curve is evidence about germline carriers and cannot bound a drug effect in either the reassuring or the alarming direction