Collecting Duct Carcinoma of Kidney: Molecular Heterogeneity Revealed by Targeted Deep Sequencing
Ying-Bei Chen, Anuradha Gopalan, Hikmat Al-Ahmadie, Samson W Fine, Helen Won, AR Brannon, Michael F Berger, Victor E Reuter, Satish K Tickoo. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: The diagnosis of collecting duct carcinoma (CDC), a rare subtype of renal cell carcinoma, is challenging; the histologic criteria proposed for CDC are partially based on exclusion and identify a group of high-grade adenocarcinomas with a spectrum of morphologic features. Molecular alterations in CDC are poorly understood.
Design: We conducted molecular characterization of 7 renal tumors that fulfilled the WHO and published diagnostic criteria for CDC. Renal medullary carcinoma was not included. DNA from frozen or formalin-fixed-paraffin embedded tissues of tumor and matched normal was analyzed by a targeted next-generation exome sequencing platform that evaluates mutations and copy number alterations in 230 cancer related genes.
Results: The study cohort included 6 men and 1 woman. Mean age was 47.2 years (33-60). Mean tumor size was 6.7 cm (2.5-11.7). All tumors were pT3, 4 of 7 had regional lymph node metastasis at time of surgery, and all developed systemic metastases. Five died from kidney cancer (mean time to death 28 months). In one case, sequencing discovered germline FH deletion in addition to somatic FH mutation, conferring a diagnosis of hereditary leiomyomatous renal cell carcinoma syndrome (HLRCC). This 38 year-old man did not have family history or concurrent cutaneous lesions, and histologic features of the tumor were not classical for HLRCC. Among the remaining 6 cases of CDC, one tumor contained a missense somatic mutation of VHL with unclear functional impact; another had a somatic TSC1 frameshift mutation; no mutations of MET, FLCN or SDHB were found. Copy number data revealed heterogenous chromosomal alteration patterns: 2 of 6 tumors harbored aberrations involving large regions of multiple chromosomes, some of which were shared (i.e. gain of 1q, loss of 11q). In contrast, the remaining 4 had either focal gains/losses, or showed no significant copy number alterations compared to normal. 22q loss (2 of 4), 10p15 gain (2 of 4) were among the focal alterations seen. No trisomy 7 or 17 was detected. Except focal 3p 21 and 3p25 losses in one tumor, no other 3p loss was identified. The amplified or lost regions suggested a role for genes regulating cell growth/proliferation, metabolism and DNA damage responses in the pathogenesis of CDC.
Conclusions: Our study suggests that histologically defined CDC is a molecularly heterogeneous group of tumors, with genetic alterations mostly distinct from other subtypes of RCC. Whether CDC represents a heterogeneous group of tumors rather than a single entity remains to be investigated.
Category: Genitourinary (including renal tumors)
Monday, March 4, 2013 8:15 AM
Proffered Papers: Section A, Monday Morning