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I am getting, in my opinion, very conflicting information from sources about the inheritance of retinoblastoma, a type of cancer. Hereditary retinoblastoma is associated with defects in the gene encoding the cell cycle-regulating, tumor suppressor protein RB1. Most sites claim that retinoblastoma is inherited in an autosomal dominant manner, which would suggest that the offspring only need one defective allele to inherit the condition. At the same time, however, all online sources claim that only one working copy of a tumor suppressor gene is required to maintain its functionality and that both copies of a tumor suppressor gene must be defective for the onset of cancer. This understanding is known as the two-hit hypothesis. But to me, this idea clearly conflicts the claim that retinoblastoma is an autosomal dominant condition and suggests the opposite: that, in order to develop retinoblastoma, there can be no working copies of the RB1 (tumor-suppressing) gene (hence making retinoblastoma an autosomal recessive disorder).

I don't know if there are any flaws in my interpretation and if somehow both explanations are correct with the issue being me not understanding it clearly. How can a condition be autosomal dominant (i.e. requiring only one affected allele) while also only requiring one working allele to prevent it? It seems illogical.

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    $\begingroup$ Welcome to Biology.SE. Please add references and/or links for your sources. In addition, it would be helpful if you included a quote from at least one of the sources claiming autosomal dominance for retinoblastoma — there may be some context you are missing. Also note that it is possible for a gene to have both dominant and recessive alleles or even for an allele to be both depending on the phenotype under consideration ... $\endgroup$
    – tyersome
    Commented Aug 19, 2022 at 4:11

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"Dominant" and "recessive" have a philosophical quality, and this makes them more confusing than an introductory course will suggest.

You could argue that Rb "really" has incomplete dominance in that Rb(+/+) embryos survive, Rb(-/-) embryos mouse embryos die at E13.5-E15.5, whereas Rb(+/-) embryos often die from tumors after birth. But from a practical point of view, if you have a patient with retinoblastoma or achondroplasia, you'll be drawing a pedigree in which anyone inheriting one copy of the gene has the same issue.

Additionally, we have the issue of cell-autonomous phenotypes. In the case of retinoblastoma, any given cell has a very low risk of losing the other copy, and you can think that at the level of the cell it is almost like it is "recessive". The risk of forming a tumor is higher, but you won't see that in any random cell under your microscope. So the phenotype in this case isn't cell-autonomous. (I haven't researched whether there is any other cue you can observe that would allow you to score single cells as Rb(+/-) on sight, but I know they don't get tumors!)

Bottom line: when describing an allele as "dominant" or "recessive" at the level of the organism, think about it from a genetic counseling point of view. Do both parents transmit the allele (or an allele that subsequently underwent mutation) to affected offspring, or just one?

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  • $\begingroup$ Hi, I think you were hinting at this in your answer though I've found a rather lucid explanation: "If a person has inherited a[n autosomal dominant] cancer susceptibility gene, it does not mean they will automatically develop cancer. It simply means that the person has inherited a mutation in a gene that gives them a higher chance to develop cancer than someone without the mutation" from urmc.rochester.edu/encyclopedia/…. Thanks a lot for the reply! $\endgroup$
    – Zuhair Qureshi
    Commented Aug 22, 2022 at 19:02
  • $\begingroup$ @ZuhairQureshi Retinoblastoma is, unfortunately, a poor example for this. The penetrance of the tumor phenotype is over 90%, and 40% of affected children develop tumors in both eyes independently. There are lower-penetrance variants of the condition, but whenever it takes only one allele to increase the chance of a tumor, it is still dominant. $\endgroup$
    – Mike Serfas
    Commented Aug 22, 2022 at 23:13
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Two-hit theory/Knudson Hypothesis is for sporadic development of retinoblastoma, once it develops it is transmitted to the offspring in an "autosomal dominant" fashion.

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  • $\begingroup$ eyewiki.aao.org/Retinoblastoma#cite_ref-Shields_text_3-1 read this for more info $\endgroup$
    – daemon
    Commented Aug 19, 2022 at 4:39
  • $\begingroup$ So the sporadic form of retinoblastoma requires both copies of the alleles to be defective, but then when transmitted to the offspring in a hereditary manner, requires only one defective allele? If not, then how are you defining " 'autosomal dominant' fashion"? I read the link you posted and it feels quite similar to what I was reading yesterday: saying the disease requires both alleles being defective to develop while still calling the disease autosomal dominant. Thanks for the help. $\endgroup$
    – Zuhair Qureshi
    Commented Aug 19, 2022 at 14:01

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