​Summary: Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. Authors of the study recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, the authors selected MUS81 c.1292G>A (p.R431H) for further investigation. 

This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, authors showed that c.1292G>A induced protein instability and affected DNA damage response. Authors suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.

Findings: Using the whole-exome sequencing approach, authors were able to identify pathogenic and likely pathogenic variants in cancer-related genes and a novel variant mapped to the DNA repair gene MUS81 associated with familial TC and BC cases. The MUS81 c.1292G>A variant was confirmed using Sanger sequencing in the index cases and their relatives. This variant was found in low frequency in an independent set of sporadic TC and BC compared to our familial cohort, as well as in healthy individuals. Applying immunohistochemistry and functional analyses, we demonstrated that MUS81 c.1292G>A disrupts protein stability and affects DNA damage response. According to our in silico PPI analysis, MUS81 is predicted to interact directly or indirectly with other cancer-related genes, which might also impact the gene penetrance. Based on these data, we suggest that MUS81 plays a role in the predisposition of familial BC and TC. Other studies are necessary in a large number of cases to confirm this association.

This study cites 2005 California Health Interview Survey (CHIS) data.