Pathogenic coding region mutations in BRCA1, BRCA2 and PALB2 are major contributors to hereditary breast cancer (HBC) but collectively explain less than a quarter of the families tested in clinical practice, leaving the majority with no identifiable genetic defect to inform cancer prevention strategies. Other HBC genes explain only a small fraction (5%) of families. In contrast to the intensive, but largely unsuccessful, international efforts aimed at discovering new HBC genes, little attention has been given to the possibility that many of these families are explained by known HBC genes but which are inactivated via alternative mechanisms that are not detected by current methodology. We hypothesize that a clinically important component of the uncovered inherited risk of breast cancer is due to inherited promoter hypermethylation. Promoter hypermethylation of specific genes in hereditary cancer syndromes have been reported, such as the MLH1 gene in a proportion of Lynch syndrome patients but whether the same mechanism explains some HBC families is largely unexplored. A significant limitation of the few studies that have tried to explore HBC is that most have used methods that interrogate single CpG dinucleotides rather than the entire gene promoter and few included cases with a strong cancer family history. To overcome the limitations of these previous attempts to resolve the role of inherited promoter hypermethylation we are performing targeted methylation sequencing (TWIST Bioscience) of the entire promoter regions of 13 HBC genes in germline DNA from over 1000 women from the BEACCON study (npj Breast Cancer 2021, 7:76) who have a very strong breast cancer family history but where all known genetic causes have been excluded. This represents the largest and most comprehensive study of its type to date, which will have the power to conclusively resolve the contribution of inherited promoter hypermethylation to HBC.

Next-generation sequencing (NGS) offers the scalability, speed, and resolution to evaluate targeted genes of interest. 靶向组合具有核心内容，有助于靶向仅需要的基因集，从而降低检测成本。MedGenome labs has been performing exome testing and targeted panel testing by NGS over the last 8 years and have so far tested more than 100,000 samples. The challenge we face in the cost sensitive Indian market is in giving low cost tests that can be used by even the lower income group. We take pride in being the first to introduce the clinical exome panel (targeting only the clinically relevant genes) to the Indian market thereby ensuring the patients get a cost-effective, at the same time, clinically productive NGS test. We have been using the TWIST comprehensive exome the last two years the content of which has been well evaluated by us. It’s content is comparable and at times better than most of the currently available exomes in the market. Our diagnostic yield with the exomes has been comparable to the other exomes we were using till then and also comparable to the published data. We are also using 10 different TWIST targeted panels which gives us a cost-effective alternative to exomes. TWIST targeted somatic panels work well with the very bad quality FFPE too, with lesser failures due to bad quality data. Our experience with the team for panel designing and troubleshooting also have been excellent. To conclude, our experience with TWIST exomes and targeted panels have been very good and it offers us a good cost-effective option needed for the cost-sensitive Indian market.

The Victorian Clinical Genetics Service is the most comprehensive provider of genomic tests in Australia. Our offering ranges from pre-conception and prenatal screening to ultra-rapid diagnostic testing, and our partnership with the Murdoch Children’s Research Institute puts a strong focus on translation of new technologies. Here we will investigate how new technology, from improved exome designs and bioinformatics to integration of transcriptomics, drives change in our routine diagnostic practise and benefits our patients.