Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk

Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer.

Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease.Methods Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided.Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4).Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations

Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease. METHODS: Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency&lt;0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR&#x2009;=&#x2009;3.19, 95% CI&#x2009;=&#x2009;1.94 to 5.25, P&#x2009;=&#x2009;8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR&#x2009;=&#x2009;6.31, 95% CI&#x2009;=&#x2009;1.83 to 21.68, P&#x2009;=&#x2009;4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR&#x2009;=&#x2009;1.88, 95% CI&#x2009;=&#x2009;1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P&#x2009;=&#x2009;5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P&#x2009;=&#x2009;3.71x10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.</p

How useful is the mutualism-parasitism continuum of arbuscular mycorrhizal functioning?

BACKGROUND A recent review in this journal puts forward the premise that our recent studies have resulted in our questioning the validity of the so-called mutualism-parasitism continuum of functioning of arbuscular mycorrhizas. This premise is incorrect and appears largely to result from a misunderstanding of terminology. SCOPE AND CONCLUSIONS We clarify a comment in one of our publications that influenced the previous review, which contains several statements that do not accurately represent our views. Our research has overturned not the continuum concept itself, but some past ideas about the balance of resources traded between AM fungi and plants. Of course, we recognize that outcomes of AM symbiosis in relation to the non-mycorrhizal (NM) state are strongly influenced by many environmental factors. Nevertheless, underlying resource trade is always a key determinant of costs and benefits of the symbiosis for both partners. In this context, we address uncertainties and contradictory ideas about mechanisms, causes, effects and outcomes in AM symbioses that occur in the literature, and issues of relevance of research at different scales. We also discuss semantics that can cause confusion. Finally, we assess how useful the mutualism-parasitism continuum is for design of hypothesis-driven experiments to disentangle the complex interactions that determine growth of AM plants, i.e. the so-called emergent properties.F. Andrew Smith & Sally E. Smit