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.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.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).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.
