Ocular Oncology Basics: Genetics

Bikramjit P Pal

Twenty first century has seen a giant leap in the understanding of human genetics. Based on human genome project humans are supposed to have roughly 20,000 to 25,000 genes
Genes are the fundamental units of heredity. To understand genetics involved in various ocular pathologies a basic understanding is essential. The following discussion will provide a overview about basic concepts in genetics and provide a glimpse into the genetics of Retinoblastoma and intraocular melanoma.

Basic structure of a chromosome [1]

 Taking the example of retinoblastoma gene lets see how a chromosome is named.


Any structural derangement in a gene is termed as mutation
Mutations can be

  1. Hereditary : In this the mutations are inherited from either of parent(who may or may not be affected) with all the cells of the index patient having the concerned mutation. Since the parent's egg or the sperm( germ cells) might have had the same mutation, it is also known as germline mutation. The index case has the chances of passing ( hereditary) it to his offspring's.
  2. Somatic: The index case has the concerned mutation in later part of its life and the concerned DNA changes are seen in the somatic cells( sparing the germ cells). There are no chances of passing it further.
  3. De novo mutations can be hereditary or somatic. In some cases the mutations occur only in the germ cells of the parent (without them being affected) which gets passed on. In another scenario the mutation occurs just after fertilization. In both such forms the affected person has the mutation afflicting all his cells and has the chances of passing it on. Interestingly even if the person has the chances of passing the mutation further on , none of his parents would have been affected as the mutation is 'de novo'.

Types of Mutation
Each amino acid is coded by group of 3 bases

  1. Missence mutation: replacement of a base pair by another: leads to a different amino acid.
  2. Nonsense mutation: a replacement of a base pair by another leading to premature stoppage in the process of coding a protein thereby forming a truncated protein.
  3. Insertion: addition of additional bases
  4. Deletion: removal of base pair without any replacement
  5. Duplication
  6. Frame shift mutation: addition or deletion of base pairs leading to altered gene's reading frame . This leads to alterations in the grouping of the base pairs forming different amino acids.
  7. Repeat expansion: Repetition of short DNA sequences in a row.

Structural chromosomal changes

Translocation: when a piece of chromosome breaks and attaches to another.
Deletion: when a part of chromosome gets lost.
Inversion: when chromosome breaks at two places and the resultant pieces gets re- inserted into opposite ends
Isochromosomes: In place of a short and long halves, the chromosome have either 2 long or 2 short halves
Dicentric chromosomes: Presence of 2 centromeres secondary to abnormal fusion.
Ring chromosomes: when chromosome breaks at two places with the resulting ends joining each other.

Degrees of Relationship

Degrees of relationship


First degree

Parents,Children,Brothers and sisters

Second degree

Grandparents, grandchildren,uncles and aunts,nephew and nieces

Third Degree


Inheritance Patterns [1]

Autosomal dominant

Autosomal Recessive

X linked dominant

X linked recessive


Genetics in Retinoblastoma [4],[5]

Retinoblastoma(RB) is one of the very few malignant ocular conditions, where having a sound knowledge of genetics provides treatment just beyond eye care.
It was the Retinoblastoma gene(RB); which was one of the earliest tumour suppressor gene to be mapped and studied which then opened the door to where we are in the current understanding of cancer genetics. The brilliant paper by Knudson[2],[3] whose theory about the 'double hit' i.e a malignant change can be observed when at least 2 'hits' or mutations take place revolutionized the science behind understanding malignancies. The RB gene has been mapped to 13q14.
RB gene functions as a tumor suppressor. Any damaged DNA is prevented from replicating further by halting the progress of cell cycle between G1 and S phase.
In the following few paragraphs the basics of retinoblastoma genetics would be dealt.
From a genetic viewpoint 3 forms of RB can be seen

Familial Retinoblastoma

Sporadic heritable Retinoblastoma

Non heritable Retinoblastoma

Few salient points

Genetics in Uveal Melanoma [6], [7]

Choroidal melanoma is the commonest ocular malignancy in adults generally occurring in the sixth decade.
Role of genetics in Uveal melanoma is a comparatively newer territory; although a very important one. Various new insights have proven the role of genetics in prognosticating a case of uveal melanoma which is a important asset not only to the physician but also for the patient.
Salient Points


1)  Help Me Understand Genetics. Genetics Home Reference - http://ghr.nlm.nih.gov. Published November 2, 2015.
2) Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996;122(3):135-40
3) Gaikwad N, Vanniarajan A, Husain A, Jeyaram I, Thirumalairaj K et al. Knudson's  hypothesis  revisited  in Indian retinoblastoma patients. Asia Pac J Clin Oncol. 2015 Dec;11(4):299-30
4) Singh AD, Damato BE, Pe'er J, Murphee AL, Perry JD. Clinical Ophthalmic Oncology .Philadelphia: Saunders, Elsevier 2007
5) Claude Houdayer, Marion Gauthier-Villars, Laurent Castéra, Laurence Desjardins, François Doz and Dominique Stoppa-Lyonnet (2012). Retinoblastoma - Genetic Counseling and Molecular Diagnosis, Retinoblastoma: An Update on Clinical, Genetic Counseling, Epidemiology and Molecular Tumor Biology, Prof. Govindasamy Kumaramanickavel (Ed.), ISBN: 978-953-51-0435-3, InTech, Available from: http://www.intechopen.com/books/retinoblastoma-an-update-on-clinical-genetic-counseling-epidemiology-andmolecular-tumor-biology/retinoblastoma-genetic-counseling-protocols-and-molecular-diagnostic-protocols.
6) Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM. Collaborative  Ocular  Oncology  Group  report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012 Aug;119(8):1596-603
7) Kivelä T, Kujala E. Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond. Eye (Lond). 2013 Feb;27(2):243-52.