Germline Mutation Screening in Patients With UTUC, Lynch Syndrome

Researchers sought to establish selection criteria for patients with upper tract urothelial carcinoma (UTUC) for Lynch syndrome (LS) screening.

Authors of a study presented at the 2022 ASCO Genitourinary Cancers Symposium explained, “Despite being a rare cancer, UTUC is the third most common core cancer associated with LS after colorectal and endometrial cancers. Yet, there is no established guideline to identify patients with UTUC who are at risk of carrying germline mutations in LS-associated genes.”

Patients with UTUC who underwent germline sequencing of ≥77 cancer susceptibility genes using next generation sequencing for a prospective tumor-normal genomic profiling imitative between April 2015 and April 2021 were eligible for the study.

“Mismatch repair protein status was evaluated by immunohistochemical (IHC) staining for MMR genes MSH2, MSH6, MLH1, and PMS2. Microsatellite instability (MSI) status was determined using next generation sequencing,” noted the authors.

The presence of germline pathogenic/likely pathogenic variants in MMR genes was used assess the diagnostic performance of clinical and tumor-based screening criteria.

The final patient sample included 232 patients with UTUC with a median diagnosis age of 67 years (43% diagnosed before the age of 65 years) and was 70% male. Of the included patients, 85% had high-grade UTUC, 12% had bilateral UTUC, and 11% has metastasis as diagnosis.

In terms of family history, 10% and 31% of participants had personal or family history of LS-associated cancers, respectively.

Key findings from the study were as follows:

• Pathogenic variants in moderate or high-penetrance genes were identified in 31 (13%) patients including 6 (3%) in BRCA1/2 and 21 (9%) in MMR genes (13 MSH2, 4 MSH6, 4 MLH1).
• 48% (10 of 21) patients with MMR pathogenic variants developed UTUC as their first cancer diagnosis.
• Of patients with MMR pathogenic variants, 94% (15 of 16) had MMR-deficient tumors and 67% (12 of 18) had MSI-high tumors.
• Personal and family history of LS core cancers (P < .001), age of diagnosis <65 years (P = .008), MSI-high (P < .001), and MMR-deficiency (P < .001) were associated with MMR carrier status.
• Current NCCN genetic referral criteria for LS has high specificity in identifying patients with LS (100%) but missed 52% patients with UTUC and MMR pathogenic variants. 

“UTUC tumor should be investigated for MMR protein and MSI status with IHC or next generation sequencing methods to augment LS-screening of patients with UTUC and inform systemic treatment selection,” concluded researchers.

Reference:
Truong H, Sheikh R, Kemel Y, et al. Defining hereditary upper tract urothelial carcinoma: Implications for genetic testing and clinical management. J Clin Oncol. 2022;40(6_suppl):523. doi:10.1200/JCO.2022.40.6_suppl.523

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