Genetics of two bladder cancer variants analyzed

Washington-Atypical histologic variants of bladder cancer are rare, comprising 5% or less of urothelial carcinomas. Atypical tumor subtypes are associated with later stage of diagnosis and worsened clinical outcomes when compared to the standard histologic variant.

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In a general session at the 2015 Society of Urologic Oncology annual meeting in Washington, Gopa Iyer, MD, of Memorial Sloan Kettering Cancer Center, New York, presented his work analyzing the genetics of two variants-plasmacytoid and adenocarcinoma-and the possible implications of these findings for clinical practice.

Plasmacytoid urothelial carcinoma is generally chemoresistant with peritoneal spread and a high rate of local recurrence after surgery.

"Histologically, it is similar to mammary lobular carcinoma and diffuse gastric carcinoma, with frequent inactivating mutations in E-cadherin,” Dr. Iyer said. He then presented representative histology showing similar morphology between these tumors and plasmacytoid urothelial carcinoma (figure).

Using targeted exon capture, Dr. Iyer and colleagues evaluated 31 plasmacytoid variant tumors and found 23 had cadherin 1 truncation mutations and three had point mutations. In those plasmacytoid tumors without obvious exon mutations, the researchers examined the methylation status of the cadherin promoter region with bisulfide sequencing and found increased methylation in four of five normal exon promoter regions.

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In total, their results would suggest a strong role for E-cadherin expression loss in the morphology and pathophysiology of plasmacytoid urothelial carcinomas. This hypothesis was further examined by taking known urothelial carcinoma cell lines and knocking out CDH1 expression. Two physical tests were then performed: a “scratch” test assaying the cell line’s ability to reform a cell sheet and a Boyden permeability assay assessing the ability of the cells to penetrate a standardized membrane. In both assays, the cells displayed differential activity compared to parietal cell lines, further supporting the hypothesis.

Next: Adenocarcinoma

Dr. Iyer then turned his attention to another urothelial carcinoma subtype: adenocarcinoma. Adenocarcinomas can arise both from the bladder proper and from the urachus. As with other infrequent subtypes, they are often found at an advanced stage. Similar to gut-based adenocarcinomas, they are responsive to 5-FU-based chemotherapy in the metastatic setting, although prognosis is poor after progression.

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Using exon capture sequencing, Dr. Iyer and and colleagues examined 16 primary bladder adenocarcinomas and 10 urachal adenocarcinomas. They found similar alteration frequencies in both categories of adenocarcinomas but more frequently found KRAS mutations (34% versus 2%) and less frequently found FGFR3 and KDM6A mutations (0% and 3% vs. 19 and 25%, respectively) when compared to standard urothelial carcinomas.

Two non-genitourinary tumor types with similar E-cadherin alterations and histologic morphology to plasmacytoid urothelial carcinomas. (Images courtesy of Gopa Iyer, MD)

Using these genetic observations, Dr. Iyer then reported on a patient treated at Memorial Sloan Kettering with metastatic urachal adenocarcinoma who underwent tumor exon sequencing that revealed GNAS and KRAS alterations. This led his physicians to trial therapy with trametinib (Mekinist), a targeted MEK inhibitor with approved indications in melanoma. To date, Dr. Iyer reports the patient has had 18 months of radiographically stable disease while on therapy.

Dr. Iyer closed his talk by reviewing two main points. He noted loss of E-cadherin expression was frequently found in plasmacytoid variant bladder cancers and that a mechanistic link likely exists for this tumor’s enhanced local migration and aggressiveness. In addition, urothelial adenocarcinomas are genomically similar to colorectal adenocarcinomas, and frequent MAPK pathway alterations may offer a therapeutic target with MEK inhibition, he said.

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