India has the highest number of retinoblastoma (RB) patients among the developing countries owing to its increasing population. Of the patients with RB, about 40% have the heritable form of the disease, making genetic analysis of the RB1 gene an integral part of disease management. However, given the large size of the RB1 gene with its widely dispersed exons and no reported hotspots, genetic testing can be cumbersome. To overcome this problem, we have developed a rapid screening strategy by prioritizing the order of exons to be analyzed, based on the frequency of nonsense mutations, deletions and duplications reported in the RB1-Leiden Open Variation Database and published literature on Indian patients. Using this strategy for genetic analysis, mutations were identified in 76% of patients in half the actual time and one third of the cost. This reduction in time and cost will allow for better risk prediction for siblings and offspring, thereby facilitating genetic counseling for families, especially in developing countries.

Retinoblastoma has an increased inheritance risk of germline RB1 mutations in offspring and siblings, especially twins. Three families, each having one retinoblastoma-affected twin, were selected for genetic analysis and DNA profiling. Germline RB1 mutations were found in all probands. DNA profiling carried on similar-looking twins of families I and II, proved them to be fraternal. This study demonstrates the importance of genetic analysis of RB1 gene for risk prediction in retinoblastoma families. It also emphasizes that DNA profiling is a mandate for genetic screening of families with twins, thus adding a new dimension in counseling of retinoblastoma.

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.

Retinoblastoma is a pediatric tumor arising in the retina with an incidence of 1 in 15000 to 18000 live births. Retinoblastoma is initiated by the inactivation of both the alleles of RB1 and it may be inherited or sporadic. There are several possible risk factors suggested for sporadic retinoblastoma including advanced paternal age.We evaluated the father's age in 42 children with retinoblastoma attending the Aravind Eye Hospital, Madurai, India from Mar 2013 to Feb 2014 retrospectively. Fathers with age 40 and above at the time of conception were included in the analysis. Patients with a positive family history were excluded from the analysis. Genetic analysis of RB1 was carried out in the tumor and blood samples of these patients of older father and their family.There were 5 patients (3 unilateral and 2 bilateral) having fathers with age 40 years and above. Genetic analysis identified RB1 mutations in the tumor samples of 4 patients and these mutations were not present in the blood samples of patient and family members. Since all these patients had somatic mutations, the involvement of paternal age impact was ruled out. In blood sample of one bilateral patient, we found de novo germline RB1 mutation possibly suggesting a role of advanced paternal age.In conclusion, the advanced paternal age seems to be a minor risk factor for retinoblastoma. Further study of large number of patients may provide a better understanding of the impact of advanced paternal age in retinoblastoma. Citation Format: Vanniarajan Ayyasamy, Namrata Gaikwad, Thirumalairaj Kannan, Aloysius A. Abraham, Veerappan Muthukkaruppan, Usha Kim. Advanced paternal age as a possible risk factor for retinoblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2766. doi:10.1158/1538-7445.AM2015-2766

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