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Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening.
Glennon, Kate I; Endo, Mikiko; Usui, Yoshiaki; Iwasaki, Yusuke; Breau, Rodney H; Kapoor, Anil; Lathrop, Mark; Tanguay, Simon; Momozawa, Yukihide; Riazalhosseini, Yasser.
Afiliação
  • Glennon KI; Department of Human Genetics, McGill University, Montreal, Canada.
  • Endo M; Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, Canada.
  • Usui Y; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Iwasaki Y; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Breau RH; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Kapoor A; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Lathrop M; University of Ottawa, Ottawa, Canada.
  • Tanguay S; Juravinski Cancer Centre, McMaster University, Hamilton, Canada.
  • Momozawa Y; Deceased.
  • Riazalhosseini Y; Department of Human Genetics, McGill University, Montreal, Canada.
JCO Precis Oncol ; 8: e2400094, 2024 Jul.
Article em En | MEDLINE | ID: mdl-39088769
ABSTRACT

PURPOSE:

Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe. MATERIALS AND

METHODS:

We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs.

RESULTS:

We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States.

CONCLUSION:

CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Testes Genéticos / Mutação em Linhagem Germinativa / Predisposição Genética para Doença / Neoplasias Renais Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: JCO Precis Oncol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Testes Genéticos / Mutação em Linhagem Germinativa / Predisposição Genética para Doença / Neoplasias Renais Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: JCO Precis Oncol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá