AbstractsBiology & Animal Science

Approximately 5-10% of breast cancer (BC) patients belong to high-risk BC families. Although mutations in BRCA1 and BRCA2 account for close to half of such families, the majority is still unexplained. The aim of this study was to identify a new BC gene by analyzing whole genome sequencing (WGS) data from one high-risk BC family without a mutation in BRCA1 and BRCA2 and screen for candidate mutations in unselected BC patients and controls. WGS had previously been performed on DNA samples from three BC patients from a high-risk BC family including five women diagnosed with the disease. The data resulting from the WGS was analyzed in the program Ingenuity® Variant AnalysisTM (IVA) where the variants were filtered based on quality, frequency, predicted deleteriousness and genetic and biological contexts. In this project the focus was set on analyzing variants predicted to result in loss-of-function (LOF) of the gene harboring them, i.e. variants that were predicted to result in protein truncation, altered splicing or binding alterations of miRNAs. Twenty-two such variants were detected in the data: eleven insertions/deletions (indels) and eleven single nucleotide polymorphisms (SNPs). Information gathered from published data and online databases on these variants led to selection of four candidate variants for further studies. These four variants were genotyped in a group of unselected BC patients and controls. One of them, a splice domain variant in the gene Atlastin GTPase 2 (ATL2 c.1129-3_1129-2insT), was significantly more frequent among unselected BC patients (minor allele frequency (MAF) = 0.83%) than controls (MAF = 0.41%), OR = 2.04 and p-value = 0.009. A high proportion (57%) of the carriers identified among the unselected BC patients had a family history of BC. Results from cDNA analysis of ATL2 in carriers and non-carriers revealed the wild type sequence only and it did not indicate altered splicing. Furthermore, analysis of a possible allelic imbalance showed no evidence of loss of heterozygosity (LOH) in tumors of carriers. The results indicate that ATL2 c.1129-3_1129-2insT is a moderate BC risk variant. However, the finding needs to be validated which might be challenging due to low frequency of the variant in other populations. This variant does not alone explain the high risk of BC in the family. Thus it can be concluded that the increased BC risk in the family is most likely explained by more than one genetic variant that jointly contribute to the risk of BC. The next steps involve searching for additional moderate to low risk variants in this family and additional families and to analyze the missense SNPs that were identified in the study but were not analyzed further in this project. Um 5-10% þeirra sem greinast með brjóstakrabbamein (BK) tilheyra fjölskyldum þar sem tíðni BK er aukin og það flokkast sem ættgengt með sterk áhrif erfðaþátta. Þrátt fyrir að stökkbreytingar í genunum BRCA1 og BRCA2 skýri tæplega helming þessara fjölskyldna þá er meirihluti þeirra ekki skýrður af þekktum erfðaþáttum.…