Genetic testing in hereditary cancer is evolving from single-gene-focused approaches in affected individuals to multi-gene panel testing for affected individuals and unaffected relatives. The widespread use of multi-gene panel testing has led to the identification of individuals with two or more pathogenic or likely pathogenic variants in hereditary cancer susceptibility genes (CSGs), termed Multilocus Inherited Neoplasia Allele Syndrome (MINAS) carriers. It remains unclear whether MINAS carriers are at increased risk of multiple, atypical, or more severe cancer phenotypes, and currently, there is no consensus on how best to identify and manage cancer risk. In this retrospective study, we identified 54 MINAS carriers at Princess Margaret Cancer Center in Toronto, Canada. Demographic, clinical, and genetic data were extracted from medical records. Group comparisons were performed using Fisher’s exact or chi-square tests for categorical variables and independent t tests for age at cancer diagnosis. Statistical significance was set at p ≤ 0.05. The majority of affected MINAS carriers had a cancer consistent with the expression of at least one pathogenic variant. Approximately 28% of MINAS carriers were diagnosed with one atypical cancer. The most frequent gene pair combinations included hereditary breast cancer genes, with some carriers exhibiting earlier age of breast cancer onset than single CSG variants reported in the literature. Our study indicates that the cancer spectrum associated with CSGs is expanding and suggests that more intensive cancer surveillance for subgroups of MINAS carriers with hereditary breast cancer CSGs may be warranted.
Orrell et al. (Thu,) studied this question.