Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families

Abstract

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1/BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1/2 mutations, as well as a potential therapeutic target, TSAd.

A Single Nucleotide Polymorphism in Catalase Is Strongly Associated with Ovarian Cancer Survival

“…DNA, from blood samples, was isolated by the Applied Genomics Technology Center (AGTC, Detroit, MI). DNA was extracted with QIAamp DNA mini kit per the manufacturer’s protocol (Qiagen, Valencia, CA) [ 27 ]. The TaqMan SNP Genotyping Assay Sets (Applied Biosystems, Carlsbad, CA) (NCBI dbSNP genome build 37, MAF source 1000 genomes) were used to genotype selected SNPs described in Table 1 .…”

Adaptor proteins: Flexible and dynamic modulators of immune cell signalling

“…Further, T cells homozygous for shorter variants of the promoter region displayed lower levels of TSAd upon TCR stimulation 151 . A non‐synonymous SNP resulting in serine to asparagine substitution at amino acid position 52 in TSAd increased susceptibility to multiple sclerosis 152 and ovarian cancer 184 . Furthermore, asparagine in position 52 of TSAd was associated with increased transcriptional activity and promoted TSAd interaction with LCK as measured by the yeast β‐galactosidase reporter assay 184 .…”

“…A non‐synonymous SNP resulting in serine to asparagine substitution at amino acid position 52 in TSAd increased susceptibility to multiple sclerosis 152 and ovarian cancer 184 . Furthermore, asparagine in position 52 of TSAd was associated with increased transcriptional activity and promoted TSAd interaction with LCK as measured by the yeast β‐galactosidase reporter assay 184 . While these reports indicate that variation in TSAd expression may influence disease susceptibility, it is unclear how specifically this may affect the risk of disease.…”

A simple and efficient workflow for generation of knock‐in mutations in Jurkat T cells using CRISPR/Cas9

“…In parallel efforts, we performed experiments to generate Jurkat T cells homozygous for the non‐synonymous single nucleotide polymorphism (SNP), rs926103, in SH2D2A . This SNP is known to affect the interaction of TSAd with LCK …”

“…This SNP is known to affect the interaction of TSAd with LCK. 15 Altogether we attempted to edit five loci in these two genes in multiple knock-in experiments. We successfully introduced knock-in mutations within exon 6 and exon 13 of the LCK gene and in exon 7 of SH2D2A.…”