Knudson's hypothesis revisited in Indian retinoblastoma patients.
OBJECTIVE
Retinoblastoma (RB) is the most common primary intraocular malignancy affecting children under 5 years of age. This study aims to correlate the clinical parameters with RB1 mutation in the light of Knudson's two-hit hypothesis in Indian RB patients.


METHODS
We analyzed the clinical details of 73 RB patients visiting Aravind Eye Hospital, Madurai, India, between January and October 2012. Data on gender, presenting age and sign, laterality, number of tumors in each eye and family history were collected. A semi log plot was derived based on Knudson's two-hit hypothesis. Genetic analysis of RB1 was carried out to identify the two hits.


RESULTS
The mean age at diagnosis for unilateral and bilateral cases was 24.0 ± 15.1 and 9.8 ± 11.5 months, respectively. Familial RB was seen in 13 (17.8%) patients of whom 11 were bilateral. Multiple tumors were observed more frequently in bilateral than in unilateral cases. All unilateral and bilateral patients followed the two-hit and one-hit curves, respectively, confirming Knudson's hypothesis in Indian patients. Genetic analysis identified two somatic mutations in tumor samples of sporadic unilateral cases. Among the two bilateral patients, one received the first hit from her father and the other patient developed a de novo germline mutation during early development.


CONCLUSIONS
The two-hit hypothesis has been reestablished in Indian patients. Genetic analysis of tumor samples has also complemented the statistical analysis to reaffirm the two hits in tumor development.
Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, India.
Namrata
N
Gaikwad
Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, India.
Ayyasamy
A
Vanniarajan
Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, India.
Akram
A
Husain
Department of Biostatistics, Lions Aravind Institute of Community Ophthalmology, Madurai, India.
Illaiyaraja
I
Jeyaram
Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, India.
Kannan
K
Thirumalairaj
Department of Pathology, Aravind Eye Hospital, Madurai, India.
Radhakrishnan
R
Santhi
Advisor-Research, Aravind Medical Research Foundation, Madurai, India.
Veerappan
V
Muthukkaruppan
Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, India.
Usha
U
Kim
D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007194:India / Q000453:epidemiology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D012175:Retinoblastoma / Q000453:epidemiology / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*
D016160:Retinoblastoma Protein
RB1 gene; childhood tumor; genetic analysis; retinoblastoma; two-hit hypothesis