Dr. Seiler began his discussion by showing that the morphological landscape of bladder cancer appears to be different in younger patients, with urothelial carcinoma being exceedingly rare in pediatric patients, while rhabdomyosarcoma, clear cell adenocarcinoma, and leiomyosarcoma being more common subtypes. To frame his discussion on the molecular differences between younger patients with bladder cancer and older patients with bladder cancer, he provided a brief review of the difference between somatic versus germline mutations. Somatic mutations are acquired during development and only affect the particular area of the body where the mutation occurred, while germline mutations occurred in the germ cells prior to fetal development. Some germline mutations confer an increased predisposition to cancer formation and are transferred to descendants.
He next discussed that we do tend to see clusters of bladder cancer in some families, but it can be difficult to discern if these are due to shared risk factors, such as environmental exposures or lifestyle choices (i.e. tobacco use), or if these are due to germline mutations within the family. Seiler noted that there is scant data looking at germline mutations in bladder cancer at present. He referenced one study in which 98 bladder cancer patients had 222 cancer-related genes sequenced. The group found that most of the germline mutations within this cohort were related to DNA repair, however, Seiler cautioned that this study was not genome-wide, and was biased because of the 222 genes sequenced, many of them were DNA repair genes.
Dr. Seiler next discussed the fact that there are currently no guidelines about when to refer younger patients who develop bladder cancer to genetic counseling. He believes that we can borrow guidelines about genetic counseling from other malignancies, however. He believes that if a patient is <50 years of age, or if they have >3 cases of breast, ovarian, pancreatic or prostate cancer in close relatives, that it is reasonable to offer genetic counseling.
He continued the discussion by reviewing what data we currently know about the differences in somatic mutations between younger and older patients and its implications. Mainly based on work from the Cancer Genome Atlas Program (TCGA), there are a few known somatic differences between older and younger patients with urothelial carcinoma. First, there appears to be an increase in mutational status of tumor suppressor genes RB1 and TP53, as well as higher neoantigen loads, and higher interferon-gamma signaling and chemokine signaling. Of the known molecular subtypes of urothelial carcinoma, the luminal papillary subtype appears to be more prevalent in younger patients. Interestingly, this luminal papillary subtype has several molecular features that make it potentially more likely to show an unfavorable response to checkpoint inhibition treatment.
He concluded his discussion that there does appear to be both somatic and germline mutational differences in younger patients who develop bladder cancer, though the data is in its infancy. Further research is needed to clarify these differences, as the underlying genetic mutations in these malignancies may influence treatment decisions. He stressed that it is important to offer genetic counseling to any bladder cancer patient under the age of 50, and those with a strong family history of known heritable malignancies. He believes that in time, a better understanding of the genetics of bladder cancer will help us to more effectively treat our patients.
Presented by: Roland Seiler, MD, Department of Urology, Inselspital, Universitätsspital Bern, Bern, Switzerland
Written by: Brian Kadow, MD. Society of Urologic Oncology Fellow, Fox Chase Cancer Center at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.