title: Tumor signatures of PTHLH overexpression, high serum calcium, and poor prognosis were observed exclusively in clear cell but not non clear cell renal carcinomas.
abstract: High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC). However, the status of serum Ca and tumor PTHLH expression have not been verified using the 2004 World Health Organization (WHO) renal tumor classification. We retrospectively reviewed corrected serum Ca levels at initial onset (n = 683) and/or as of recurrence (n = 71) in patients with RCC. We also examined a total of 623 renal parenchymal tumor samples for PTHLH mRNA expressions by quantitative real-time PCR. High serum Ca concomitant with PTHLH overexpression in tumors was observed exclusively in clear cell RCC but not in other non clear cell subtype tumors, including papillary, chromophobe, collecting-duct, unclassified, and other rare subtype RCCs or in benign oncocytomas and angiomyolipomas. In clear cell RCC, PTHLH expression was significantly high in male patients, and was associated with a symptomatic presentation, higher grade, and higher stage cases, whereas it was not associated with VHL gene status. Univariate analyses demonstrated that high PTHLH expression was strongly associated with poor outcome both in overall survival (OS) and disease-free survival (DFS) for patients who underwent standard nephrectomy. Further multivariate Cox analyses revealed that the PTHLH expressions remained as independent prognostic parameters for OS but not for DFS. These data suggest that the previously characterized tumor signatures of high serum Ca due to high PTHLH expression and poor prognosis are clear cell RCC-specific features, whereas these characteristics are rare in non clear cell RCCs.
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.forename: Takayuki
authors.initials: T
authors.lastname: Murakami
authors.forename: Koichi
authors.initials: K
authors.lastname: Shioi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Mizuno
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ito
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.forename: Futoshi
authors.initials: F
authors.lastname: Sano
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Makiyama
authors.forename: Noboru
authors.initials: N
authors.lastname: Nakaigawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kishida
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kubota
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009392:Nephrectomy; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D002118:Calcium
keywords: Gene expression; PTHLH; prognosis; qRT-PCR; renal cell carcinoma; serum calcium