Additional file 1: Table S1. of De novo mutational profile in RB1 clarified using a mutation rate modeling algorithm

All de novo germline variants in RB1 gene of patients with RB. “gDNA position” is the nucleotide position in the GENBANK accession number L11910 of the gene. Table S2. All ExAC variants in RB1 gene that were considered in our analysis. “gDNA position” is the nucleotide position in the GENBANK accession number L11910 of the gene. Table S3. All Nonsense variants in RB1 gene from Onadim and Houdayer groups. “gDNA position” is the nucleotide position in the GENBANK accession number L11910 of the gene. Table S4. Comparison of observed mutations and the simulated frequency of nonsense changes per exon, to find differential pathogenicity within nonsense mutations. Analysis was performed on data from Onadim and Houdayer groups. Table S5. Comparison of observed mutations and the simulated frequency of nonsense changes to find differential pathogenicity within nonsense mutations. Data shown for all amino acids and two arginine codons (99% CI) which can change to a stop codon. Analysis was performed on data from Onadim and Houdayer groups. Table S6. Polyphen predictions on the de novo germline missense mutations or some potential variants near codon 661 in RB1 gene. “Polyphen2_format” is the variant format accepted by the Polyphen2 tool. “Polyphen_prediction” is the result of Polyphen2 on the missense variant. Table S7. Comparison between observed mutations and the simulated frequency of missense changes at amino acids and codons in exon 20, to find localized pathogenicity within missense mutations. Only the significant results are reported here. Table S8. Genomic territory of RB1 gene analyzed in our study. “Position Start” is the start position of the entry as per GENBANK database. “Position End” is the end positon of the entry as per GENBANK database. “Annotation” is the description of the entry. Possible keywords are exon or donor/acceptor region in essential splice or nonessential intronic region. “Exon” corresponds to exon number of the entry. (XLSX 30 kb

Additional file 3: Figure S2. of De novo mutational profile in RB1 clarified using a mutation rate modeling algorithm

Donor splice mutations in Exons 5, 6 and 12, and their effect on codon structure. The codon structures are shown prior and after the donor splice mutation. The donor splice mutation results in exon skipping or deletion, but can also cause a frameshift mutation in certain cases. (PDF 84 kb

Additional file 1: of A case–control study of sporadic retinoblastoma in relation to maternal health conditions and reproductive factors: a report from the Children’s Oncology group

Table S1. Multiple imputation/propensity score analysis of retinoblastoma in relation to maternal medical conditions and prescription drug use which occurred in the month before or during the pregnancy. Table S2. Multiple imputation/propensity score analysis of associations between maternal pregnancy history, body size, and breastfeeding with retinoblastoma using unconditional logistic regression. Table S3. Multiple imputation/propensity score analysis of sporadic retinoblastoma in relation to the mother’s birth control use and fertility treatment. (DOC 141 kb

Demographic characteristics of mothers of the unilateral cases and matched controls.

<p>Demographic characteristics of mothers of the unilateral cases and matched controls.</p

Environmental tobacco exposure of mother during pregnancy and unilateral retinoblastoma (Conditional logistic regression analysis).

<p>Environmental tobacco exposure of mother during pregnancy and unilateral retinoblastoma (Conditional logistic regression analysis).</p

Sporadic Retinoblastoma and Parental Smoking and Alcohol Consumption before and after Conception: A Report from the Children’s Oncology Group

<div><p>Background</p><p>Retinoblastoma is the most frequent tumor of the eye in children and very little is known about the etiology of non-familial (sporadic) retinoblastoma. In this study we examined whether parental tobacco smoking or alcohol consumption (pre- or post-conception) contribute to the two phenotypes (bilateral or unilateral) of sporadic retinoblastoma.</p><p>Methods</p><p>Two large multicenter case-control studies identified 488 cases through eye referral centers in the United States and Canada or through the Children’s Oncology Group. Controls (n = 424) were selected from among friends and relatives of cases and matched by age. Risk factor information was obtained via telephone interview. We employed multivariable logistic regression to estimate the effects of parental tobacco smoking and alcohol consumption on retinoblastoma.</p><p>Findings</p><p>Maternal smoking before and during pregnancy contributed to unilateral retinoblastoma risk in the child: year before pregnancy conditional Odds Ratio (OR), 8.9; 95% confidence interval (CI) 1.5–51, and unconditional OR, 2.4; 95% CI, 1.3–4.7; month before or during pregnancy, conditional OR, 3.3; 95% CI, 0.5–20.8, and unconditional OR, 2.8; 95% CI, 1.1–7.0. No association was found for maternal or paternal alcohol consumption.</p><p>Conclusion</p><p>The results of this study indicate that maternal active smoking during pregnancy may be a risk factor for sporadic retinoblastoma. Our study supports a role for tobacco exposures in embryonal tumors.</p></div

Demographic characteristics of fathers of the bilateral cases and matched controls.

<p>Demographic characteristics of fathers of the bilateral cases and matched controls.</p

Paternal smoking and alcohol consumption and bilateral retinoblastoma (Conditional logistic regression).

<p>Paternal smoking and alcohol consumption and bilateral retinoblastoma (Conditional logistic regression).</p

Maternal smoking and drinking consumption and unilateral retinoblastoma (Conditional logistic regression).

<p>Maternal smoking and drinking consumption and unilateral retinoblastoma (Conditional logistic regression).</p

Mutation Spectrum of <i>RB1</i> Gene in Unilateral Retinoblastoma Cases from Tunisia and Correlations with Clinical Features

<div><p>Retinoblastoma, an embryonic neoplasm of retinal origin, is the most common primary intraocular malignancy in children. Somatic inactivation of both alleles of the <i>RB1</i> tumor suppressor gene in a retinal progenitor cell through diverse mechanisms including genetic and epigenetic modifications, is the crucial event in initiation of tumorigenesis in most cases of isolated unilateral retinoblastoma. We analyzed DNA from tumor tissue and from peripheral blood to determine the <i>RB1</i> mutation status and seek correlations with clinical features of 37 unrelated cases of Tunisian origin with sporadic retinoblastoma. All cases were unilateral except one who presented with bilateral disease, in whom no germline coding sequence alteration was identified. A multi-step mutation scanning protocol identified bi-allelic inactivation of <i>RB1</i> gene in 30 (81%) of the samples tested. A total of 7 novel mutations were identified. There were three tumors without any detectable mutation while a subset contained multiple mutations in <i>RB1</i> gene. The latter group included tumors collected after treatment with chemotherapy. There were seven individuals with germline mutations and all presented with advanced stage of tumor. There was no difference in age of onset of RB based on the germline mutation status. Thus 20% of the individuals with sporadic unilateral RB in this series carried germline mutations and indicate the importance of genetic testing all children with sporadic retinoblastoma. These findings help to characterize the spectrum of mutations present in the Tunisian population and can improve genetic diagnosis of retinoblastoma.</p></div