The prevalence of BRCA(1/2) mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA(1/2) changes, given the ...sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.
In 235 unselected ovarian cancers, BRCA(1/2) was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA(1/2) transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA(1/2) mutations, germline DNA was sequenced.
Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA(1/2) mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA(1/2) mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio HR = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA(1/2) deficiency, defined as BRCA(1/2) mutations or expression loss (in 24 13.3% BRCA(1/2)-wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses.
BRCA(1/2) somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.
Mutation screening of the breast and ovarian cancer–predisposition genes
BRCA1 and
BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence ...variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in
trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an “average” deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100:1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20:1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and
in silico analyses.
Acetylation of the N-terminal tails of the core histones directly facilitates the recognition by TFIIIA of the 5S RNA gene within model chromatin templates. This effect is independent of a reduction ...in the extent of histone-DNA interactions or a change in DNA helical repeat; it is also independent of whether a histone tetramer or octamer inhibits TFIIIA binding. Removal of the N-terminal tails from the core histones also facilitates the association of TFIIIA with nucleosomal templates. We suggest that the histone tails have a major role in restricting transcription factor access to DNA and that their acetylation releases this restriction by directing dissociation of the tails from DNA and/or inducing a change in DNA configuration on the histone core to allow transcription factor binding. Acetylation of core histones might be expected to exert a major influence on the accessibility of chromatin to regulatory molecules.
Histone-DNA contacts within a nucleosome influence the function of trans-acting factors and the molecular machines required to activate the transcription process. The internal architecture of a ...positioned nucleosome has now been probed with the use of photo-activatable cross-linking reagents to determine the placement of histones along the DNA molecule. A model for the nucleosome is proposed in which the winged-helix domain of the linker histone is asymmetrically located inside the gyres of DNA that also wrap around the core histones. This domain extends the path of the protein superhelix to one side of the core particle.
10533 Background: Accurate BC risk assessment is essential to identify women for whom screening and preventive interventions may be lifesaving. Incorporation of PRS into clinical models can improve ...risk prediction, but most PRS have shown suboptimal performance among non-Europeans. We previously described a multiple-ancestry PRS (MA-149) based on 56 ancestry-informative and 93 BC-associated single-nucleotide polymorphisms (SNPs). MA-149 achieved accuracy for diverse populations by characterizing genetic ancestry at each SNP in terms of fractions attributable to reference ancestries (African, East Asian, European) and applying ancestry-specific risks and frequencies. MA-149 significantly outperformed the Tyrer-Cuzick (TC) model, and integration of MA-149 with TC improved predictive accuracy by roughly two-fold over TC alone. Here, we aimed to improve MA-149 by expanding the set of BC SNPs and refining ancestry-specific risks. Methods: We developed a novel stepwise regression methodology accounting for linkage disequilibrium to select an optimal set of BC SNPs. Women referred for hereditary cancer testing and negative for pathogenic variants in BC genes were divided into consecutive cohorts to (1) refine ancestry-specific SNP risks ( N=58,191 Black/African; N=27,160 East Asian), (2) develop the PRS ( N=184,322), and (3) conduct independent validation ( N=146,110). Predictive accuracy and calibration of the new PRS were evaluated in the full cohort and subpopulations of different ancestries. Odds ratios (OR) from multivariable regression are reported per standard deviation. Results: A set of 385 SNPs (56 ancestry, 329 BC) was selected for the new PRS (MA-385). MA-385 improved upon clinical factors and outperformed MA-149 within each ancestry (Table). Among non-Europeans, MA-385 was a better BC risk predictor (OR=1.47, 95% CI: 1.42-1.52) than MA-149 (OR=1.40, 95% CI: 1.35-1.45). The strongest associations were observed in Ashkenazi Jewish and Hispanic women (Table). MA-385 identified more women at >2-fold increased risk than MA-149 (6.5 % vs 2%). Goodness-of-fit tests showed that MA-385 was well-calibrated while a 385-SNP PRS with European weights was miscalibrated for non-Europeans. Conclusions: MA-385 was well-calibrated, improved upon clinical factors, and outperformed existing PRS in all tested ancestries. Incorporation of MA-385 into risk assessment could improve the early detection and prevention of BC. Table: see text
The recent surge of discoveries concerning the structural organization of nucleosomes, together with genetic evidence of highly specialized roles for the histones in gene regulation, have brought a ...renewed need for a detailed understanding of nucleosomal anatomy. Here we review recent structural advances leading to a new level of understanding of the nucleosome and chromatin fibre structure. We discuss the problems and challenges for existing models of chromatin structure and, in particular, consider how linker histones may bind within the nucleosome, together with the implications of their association for the structure of the chromatin fibre.
Abstract Background: Common genetic variants, mainly single-nucleotide polymorphisms (SNPs) explain substantial genetic susceptibility to BC. PRS have been developed to quantify the combined effects ...of BC-associated SNPs, providing important information about BC risk. Historically, genome-wide association studies have been conducted in predominantly European populations, resulting in miscalibrated and inaccurate PRS for non-Europeans. We previously described a multiple-ancestry PRS (MA-PRS-149) based on 56 ancestry-informative and 93 BC-associated SNPs. The MA-PRS-149 achieved accuracy for all women by characterizing the genetic ancestry of each BC-associated SNP in terms of three reference ancestries (African, East Asian, and European), applying ancestry-specific SNP risks and frequencies, and combining the results as a weighted sum of three ancestry-specific PRS. Here, we aimed to improve the predictive accuracy of MA-PRS-149, particularly for non-Europeans, through the inclusion of additional BC-associated SNPs. Methods: Women referred for hereditary cancer testing and negative for pathogenic variants in BC-associated genes were divided into consecutive study cohorts to (1) quantify ancestry-specific SNP risks, (2) combine the three ancestry-specific PRS, and (3) pre-specified clinical validation. To select an optimal set of BC-associated SNPs, we developed a novel synthetic stepwise regression methodology that accounts for linkage disequilibrium. Ancestry-specific SNP risks were determined from meta-analyses of literature with clinical cohorts of 57,827 Black/African and 26,992 East Asian women. Ancestry-specific PRS were combined based on a diverse cohort of 157,740 women. Clinical validation was conducted in an independent cohort of 77,774 women. We used multivariable logistic regression adjusted for age, ancestry, and cancer history to test for improved BC risk prediction over clinical factors. We tested for improvement over the MA-PRS-149, and a European PRS, by including additional PRS as covariates. Calibration was assessed through goodness-of-fit tests. All analyses were conducted within the full cohort and ancestral subpopulations. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported per standard deviation within the corresponding population. Results: An optimal set of 383 SNPs (56 ancestry-informative and 327 BC-associated) was included in the final PRS (MA-PRS-383). MA-PRS-383 added significant predictive information to clinical factors in the full cohort and within each ancestry (Table 1). MA-PRS-383 had greater predictive accuracy than MA-PRS-149 or a 383-SNP PRS with European weights. Goodness-of-fit tests showed that MA-PRS-383 was well-calibrated and predicted risk accurately in the tails of the distribution for both European and non-European women. Conclusion: MA-PRS-383 was well-calibrated and substantially improved upon existing PRS in all tested ancestral populations. Incorporation of MA-PRS-383 into BC risk assessment may lead to more accurate identification of women who are most likely to benefit from screening and preventive medications. Citation Format: Timothy Simmons, Elisha Hughes, Dmitry Pruss, Matthew Kucera, Benjamin Roa, Thaddeus Judkins, Thomas Slavin, Victor Abkevich, Ryan Hoff, Srikanth Jammulapati, Susanne Wagner, Dale Muzzey, Jerry Lanchbury, Alexander Gutin. A second-generation polygenic risk score (PRS) based on genetic ancestry improves breast cancer (BC) risk prediction for all ancestries abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-07.
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