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Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer

Lotan, Tamara L. ; Kaur, Harsimar B. ; Salles, Daniela C. ; Murali, Sanjana ; Schaeffer, Edward M. ; Lanchbury, Jerry S. ; Isaacs, William B. ; Brown, Robert ; Richardson, Andrea L. ; Cussenot, Olivier ; Cancel-Tassin, Geraldine ; Timms, Kirsten M. ; Antonarakis, Emmanuel S.

Modern pathology, 2021-06, Vol.34 (6), p.1185-1193 [Periódico revisado por pares]

United States: Elsevier Inc

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Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer
Autor: Lotan, Tamara L. ; Kaur, Harsimar B. ; Salles, Daniela C. ; Murali, Sanjana ; Schaeffer, Edward M. ; Lanchbury, Jerry S. ; Isaacs, William B. ; Brown, Robert ; Richardson, Andrea L. ; Cussenot, Olivier ; Cancel-Tassin, Geraldine ; Timms, Kirsten M. ; Antonarakis, Emmanuel S.
Assuntos: Adult ; Aged ; Allelic Imbalance - genetics ; Ataxia Telangiectasia Mutated Proteins - genetics ; Biomarkers, Tumor - genetics ; BRCA1 protein ; BRCA2 protein ; BRCA2 Protein - genetics ; FDA approval ; Genomic instability ; Genomic Instability - genetics ; Germ-Line Mutation - genetics ; Heterozygosity ; Homologous recombination ; Humans ; Loss of Heterozygosity - genetics ; Male ; Middle Aged ; Mutation ; Ovarian carcinoma ; p53 Protein ; Poly(ADP-ribose) polymerase ; Prostate cancer ; Prostatic Neoplasms - genetics ; Tumors
É parte de: Modern pathology, 2021-06, Vol.34 (6), p.1185-1193
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SourceType-Scholarly Journals-1
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Descrição: The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer

Lotan, Tamara L. ; Kaur, Harsimar B. ; Salles, Daniela C. ; Murali, Sanjana ; Schaeffer, Edward M. ; Lanchbury, Jerry S. ; Isaacs, William B. ; Brown, Robert ; Richardson, Andrea L. ; Cussenot, Olivier ; Cancel-Tassin, Geraldine ; Timms, Kirsten M. ; Antonarakis, Emmanuel S.

United States: Elsevier Inc

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