Redefining the Bladder Cancer Phenotype using Patterns of Familial Risk

Relatives of bladder cancer (BCa) patients have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking related behaviors that may concentrate in some families. We demonstrate a new method to simultaneously assess risks for multiple cancers to identify distinct multi-cancer configurations (multiple different cancer types that cluster in relatives) surrounding BCa patients. We identified 6,416 individuals with urothelial carcinoma and familial information using the Utah Cancer Registry and Utah Population Database (UPDB). First-degree relatives, second-degree relatives, and first cousins were used to construct a familial enrichment matrix for cancer-types previously shown to be individually associated with BCa. K-medioids clustering were used to identify Familial Multi-Cancer Configurations (FMC). A case-control design and Cox regression with a 1:5 ratio of BCa cases to cancer-free controls was used to quantify the risk in specific relative-types and spouses in each FMC. Clustering analysis revealed 12 distinct FMCs, each exhibiting a different pattern of cancer co-aggregation. Of the 12 FMCs, four exhibited strong familial risk of bladder cancer along with specific patterns of increased risk of cancers in other sites (BCa FMCs), and were the focus of further investigation. Cancers at increased risk in these four BCa FMCs most commonly included melanoma, prostate and breast cancer and less commonly included leukemia, lung, pancreas and kidney cancer. A network-based approach can be used with familial data to discover new phenotype clusters for BCa, providing new directions for discovering patterns of cancer clustering.