ASCO 2017: Cancer predisposing germline mutations in patients with urothelial cancer of the renal pelvis, ureter and bladder

Chicago, IL ( Heritable genes in urothelial cancers (UC) have not been studied extensively, except for the mismatch-repair pathway (MMR) (e.g. MSH2) typically associated with primary UC involving the renal pelvis/ureter (Lynch syndrome). According to epidemiologic studies, 30% of UC have some heritable fraction. It is known that family history confers a 2-fold increased risk in bladder UC. On top of that, in UC patients the prevalence of germline mutations in cancer predisposing genes has not been studied thoroughly. Therefore, Dr. Carlo presented a study attempting to investigate the prevalence of known cancer pre-disposing germline mutations in UC patients.

In this study, patients with UC involving bladder, ureter and renal pelvis, unselected for suspicion of inherited cancer syndrome, were prospectively enrolled from medical oncology and urology clinics to a germline sequencing protocol from June 2016 to April 2017. Germline gene analysis was performed using a next generation sequencing (NGS) platform (MSK-IMPACT) that analyzes tumor-normal DNA pairs. The germline gene panel consisted of 76 genes associated with hereditary cancer predisposition.

A total of 113 patients had NGS results, with a median age of 63 (31-87), 78% male, 22% female. Primary sites were bladder in 76 patients and renal pelvis/ureter in 35 patients. 73% had organ-confined disease and 27% had metastases. 8 patients had early onset (≤45 yrs at diagnosis), and germline mutations were found in 22% of patients with 20% having only 1 germline mutations and 2% having 2 germline mutations. Most germline mutations were in the DNA damage response (DDR) genes (58%) and not in the MMR genes (31%). The germline mutations were mostly of high penetrance (BRCA 1 & 2, MMR genes, TP53 and FH).

There are currently no recommendation by the American College of Medical Genetics and Genomics (ACMG) and the NCCN about genetic screening for UC. There are however, Lynch associated cancer recommendations for renal pelvis/ureter UC. Taking the results of this study, Dr. Carlo concluded that there is a high prevalence of germline genetic mutations in UC. MMR and DDR are the most frequent mutations and may have a role in pathogenicity. These findings could potentially have profound implications for cancer screening of relevant patients and their families.

Presented By: Maria Isabel Carlo, Memorial Sloan Kettering Cancer Center, New York, NY

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
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