Accurate estimation of systemic tumor load from the blood of cancer patients has enormous potential. One avenue is to measure the presence of cell-free circulating tumor DNA in plasma. Various ...approaches have been investigated, predominantly covering hotspot mutations or customized, patient-specific assays. Therefore, we investigated the utility of using exome sequencing to monitor circulating tumor DNA levels through the detection of single nucleotide variants in plasma. Two technologies, claiming to offer efficient library preparation from nanogram levels of DNA, were evaluated. This allowed us to estimate the proportion of starting molecules measurable by sequence capture (<5%). As cell-free DNA is highly fragmented, we designed and provide software for efficient identification of PCR duplicates in single-end libraries with a varying size distribution. On average, this improved sequence coverage by 38% in comparison to standard tools. By exploiting the redundant information in PCR-duplicates the background noise was reduced to ∼1/35,000. By applying our optimized analysis pipeline to a simulation analysis, we determined the current sensitivity limit to ∼1/2400, starting with 30 ng of cell-free DNA. Subsequently, circulating tumor DNA levels were assessed in seven breast- and one prostate cancer patient. One patient carried detectable levels of circulating tumor DNA, as verified by break-point specific PCR. These results demonstrate exome sequencing on cell-free DNA to be a powerful tool for disease monitoring of metastatic cancers. To enable a broad implementation in the diagnostic settings, the efficiency limitations of sequence capture and the inherent noise levels of the Illumina sequencing technology must be further improved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden CAncer of the Prostate in Sweden (CAPS) using ...Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.
In January 2012, the European Commission presented the draft of a new General Data Protection Regulation (GDPR) to the European Parliament and the Council of the European Union. This new binding ...Regulation will lay the legal foundation for future European epidemiology based on personal data, including register-based research.
Single-nucleotide polymorphisms (SNPs) in chromosomal regions 8q and 17q are associated with susceptibility to prostate cancer, although each SNP has only a modest association with the disease. This ...study identified five SNPs in these chromosomal regions that had a strong association with prostate cancer when combined. The strength of the association increased with the number of prostate-cancer–associated SNPs in the genome. The addition of a positive family history gave an even greater association. This study shows how weak associations between genetic variants and a disease that have been found in genomewide association studies can be strengthened through combinatorial analysis.
This study identified five SNPs in chromosomal regions 8q and 17q that had a strong association with prostate cancer when combined. The strength of the association increased with the number of prostate-cancer–associated SNPs in the genome.
Genomewide association studies of complex diseases have identified sequence variants that are consistently associated with the risk of such diseases.
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Often such variants have limited use in the assessment of disease risk in an individual patient, since most of them confer a relatively small risk. Whether combinations of individual variants confer larger, more clinically useful associations with increased risk remains to be shown.
Age, race, and family history are three factors that have a consistent association with the risk of prostate cancer.
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A meta-analysis showed a pooled odds ratio of 2.5 for men who had a first-degree relative with the . . .
Many men with lethal prostate cancer did not undergo prostate-specific antigen (PSA) testing before diagnosis, or if they did, were not subsequently followed up. This could implicate deficiencies in ...current opportunistic PSA testing strategies.
Prostate cancer (PC) is the fifth leading cause of cancer-related mortality in men worldwide. Opportunistic testing with prostate-specific antigen (PSA) has limited impact on PC mortality. Our objective was to assess prediagnostic PSA testing patterns and clinical characteristics at diagnosis in men with lethal PC.
We conducted a population-based observational study of all men dying from PC in Stockholm County, Sweden, from 2015 to 2019. Data were retrieved from the National Prostate Cancer Register and the Stockholm PSA and Biopsy Register. If the first PSA was registered within 1 yr before diagnosis, men were categorised as PSA naïve. If an elevated PSA level was registered >1 yr before diagnosis without leading to prostate biopsy or repeating PSA within 1 yr, men were categorised as having delayed diagnosis. If a normal PSA level was registered within 5 yr before diagnosis, followed by an elevated PSA level that resulted in PC diagnosis within 1 yr, men were categorised as PSA tested. Clinical characteristics at diagnosis were stratified with D’Amico risk group classification.
Among 1473 men dying from PC, PSA test history was available for 995. Of these men, 60% (n = 592) were PSA naïve, 25% (n = 250) received delayed diagnosis, and 15% (n = 153) were PSA tested. After examining all 1473 men, 25% (n = 350) were diagnosed with low- or intermediate-risk cancer, 48% (n = 687) with high-risk cancer, and 27% (n = 385) with metastatic disease. Limitations include the retrospective design.
Many men with lethal PC lacked PSA testing before diagnosis or had been tested without subsequent follow-up. Nearly half of the study population was diagnosed with high-risk cancer and almost one-third with metastatic disease. These findings suggest further evaluation of the current opportunistic PSA testing approach.
Data from a population-based observational study of men dying from prostate cancer showed that many of them did not undergo either prostate-specific antigen (PSA) testing before diagnosis or subsequent follow-up if tested. These findings implicate deficiencies in the current opportunistic PSA testing approach.
Abstract Background Robot-assisted radical prostatectomy (RARP) is an increasingly commonly used surgical treatment option for prostate cancer (PCa); however, its longer-term oncologic results remain ...uncertain. Objective To report biochemical recurrence–free survival (BRFS) outcomes for men who underwent RARP ≥5 yr ago at a single European centre. Design, setting, and participants A total of 944 patients underwent RARP as monotherapy for PCa from January 2002 to December 2006 at Karolinska University Hospital, Stockholm, Sweden. Standard clinicopathologic variables were recorded and entered into a secure, ethics-approved database made up of those men with registered domiciles in Stockholm. The median follow-up time was 6.3 yr (interquartile range: 5.6–7.2). Outcome measurements and statistical analysis The outcome of this study was biochemical recurrence (BCR), defined as a confirmed prostate-specific antigen (PSA) of ≥0.2 ng/ml. Kaplan-Meier survival plots with log-rank tests, as well as Cox univariable and multivariable regression analyses, were used to determine BRFS estimates and determine predictors of PSA relapse, respectively. Results and limitations The BRFS for the entire cohort at median follow-up was 84.8% (95% confidence interval CI, 82.2–87.1); estimates at 5, 7, and 9 yr were 87.1% (95% CI, 84.8–89.2), 84.5% (95% CI, 81.8–86.8), and 82.6% (95% CI, 79.0–85.6), respectively. Nine and 19 patients died of PCa and other causes, respectively, giving end–of–follow-up Kaplan-Meier survival estimates of 98.0% (95% CI, 95.5–99.1) and 94.1% (95% CI, 90.4–96.4), respectively. Preoperative PSA >10, postoperative Gleason sum ≥4 + 3, pathologic T3 disease, positive surgical margin status, and lower surgeon volume were associated with increased risk of BCR on multivariable analysis. This study is limited by a lack of nodal status and tumour volume, which may have confounded our findings. Conclusions This case series from a single, high-volume, European centre demonstrates that RARP has satisfactory medium-term BRFS. Further follow-up is necessary to determine how this finding will translate into cancer-specific and overall survival outcomes.
Interval breast cancer is of clinical interest, as it exhibits an aggressive phenotype and evades detection by screening mammography. A comprehensive picture of somatic changes that drive tumors to ...become symptomatic in the screening interval can improve understanding of the biology underlying these aggressive tumors.
Initiated in April 2013, Clinical Sequencing of Cancer in Sweden (Clinseq) is a scientific and clinical platform for the genomic profiling of cancer. The breast cancer pilot study consisted of women diagnosed with breast cancer between 2001 and 2012 in the Stockholm/Gotland regions. A subset of 307 breast tumors was successfully sequenced, of which 113 were screen-detected and 60 were interval cancers. We applied targeted deep sequencing of cancer-related genes; low-pass, whole-genome sequencing; and RNA sequencing technology to characterize somatic differences in the genomic and transcriptomic architecture by interval cancer status. Mammographic density and PAM50 molecular subtypes were considered.
In the univariate analyses,
, and
were significantly more frequently mutated in interval cancers than in screen-detected cancers. Acquired somatic copy number aberrations with a frequency difference of at least 15% between the two groups included gains in 17q23-q25.3 and losses in 16q24.2. Gene expression analysis identified 447 significantly differentially expressed genes, of which 120 were replicated in an independent microarray dataset. After adjusting for PAM50, most differences were no longer significant.
Molecular differences by interval cancer status were observed, but they were largely explained by PAM50 subtypes. This work offers new insights into the biological differences between the two tumor groups.
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Breast cancer patients with BRCA1/2‐driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose ...of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi‐Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety‐two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.
What's new?
In order to provide personalized therapy to patients with pathogenic BRCA1/2 variants, it's necessary to find them. Currently, patients are screened based on risk factors, such as family history. How many BRCA1/2 carriers are missed? What if everyone were screened? Here, the authors sequenced DNA from more than 5,000 Swedish breast cancer patients looking for pathogenic BRCA1/2 variants, and they found 92 carriers. Of these, only 35 had been identified by clinical screening. 60% of cancer‐causing BRCA variants had not been detected. This is one of the largest population‐based studies to date examining BRCA1/2 prevalence.
Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; ...however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10⁻⁸ under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.
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