DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men

Abstract

Background: Altered DNA damage response (DDR) has emerged as an important mechanism for the development of aggressive prostate cancer among men of European ancestry but not other ancestry groups. Because common mechanisms for aggressive disease are expected, we explored a large panel of DDR genes and pathways to demonstrate that DDR alterations contribute to development of aggressive prostate cancer in both African American and European American men.

Methods: We performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher's exact tests. Secondary analysis examined if carrier frequencies differed by ancestry.

Results: Lethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10^-4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02).

Conclusions: Our findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.

Figure 1.

Carrier frequencies of pathogenic sequence variants in lethal and indolent cases summarized by DNA damage response (DDR) pathway. A) Full DDR gene panel. B) DDR gene panel excluding BRCA2. C) Gene panel from Pritchard et al (3). BER = base excision repair; DR = direct repair; FA = Fanconi anemia; HR = homologous recombination; MMR = mismatch repair; NER = nucleotide excision repair; NHEJ = nonhomologous end joining; TLS = translesion synthesis.

Figure 2.

Carrier frequencies of pathogenic sequence variants in lethal cases diagnosed younger than 65 years, lethal cases diagnosed at 65 years and older, and indolent cases summarized by DNA damage response (DDR) pathway. BER = base excision repair; DR = direct repair; FA = Fanconi anemia; HR = homologous recombination; MMR = mismatch repair; NER = nucleotide excision repair; NHEJ = nonhomologous end joining; TLS = translesion synthesis.

Figure 3.

Carrier frequencies of the most likely pathogenic variants among the variants of unknown clinical significance in lethal and indolent cases summarized by DNA damage response (DDR) pathway. BER = base excision repair; DR = direct repair; FA = Fanconi anemia; HR = homologous recombination; MMR = mismatch repair; NER = nucleotide excision repair; NHEJ = nonhomologous end joining; TLS = translesion synthesis.