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Fulltext Treatment of Patients With Early-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline

Costas-Chavarri A, Nandakumar G, Temin S, Lopes G, Cervantes A, Cruz Correa M, et al.

J Glob Oncol, 2019 02;5:1-19.
PMID: 30802158 DOI: 10.1200/JGO.18.00214

PURPOSE: To provide resource-stratified, evidence-based recommendations on the treatment and follow-up of patients with early-stage colorectal cancer.
METHODS: ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus process with additional experts for one round of formal ratings.
RESULTS: Existing sets of guidelines from 12 guideline developers were identified and reviewed; adapted recommendations from six guidelines form the evidence base and provide evidence to inform the formal consensus process, which resulted in agreement of 75% or more on all recommendations.
RECOMMENDATIONS: For nonmaximal settings, the recommended treatments for colon cancer stages nonobstructing, I-IIA: in basic and limited, open resection; in enhanced, adequately trained surgeons and laparoscopic or minimally invasive surgery, unless contraindicated. Treatments for IIB-IIC: in basic and limited, open en bloc resection following standard oncologic principles, if not possible, transfer to higher-level facility; in emergency, limit to life-saving procedures; in enhanced, laparoscopic en bloc resection, if not possible, then open. Treatments for obstructing, IIB-IIC: in basic, resection and/or diversion; in limited or enhanced, emergency surgical resection. Treatment for IIB-IIC with left-sided: in enhanced, may place colonic stent. Treatment for T4N0/T3N0 high-risk features or stage II high-risk obstructing: in enhanced, may offer adjuvant chemotherapy. Treatment for rectal cancer cT1N0 and cT2n0: in basic, limited, or enhanced, total mesorectal excision principles. Treatment for cT3n0: in basic and limited, total mesorectal excision, if not, diversion. Treatment for high-risk patients who did not receive neoadjuvant chemotherapy: in basic, limited, or enhanced, may offer adjuvant therapy. Treatment for resectable cT3N0 rectal cancer: in enhanced, base neoadjuvant chemotherapy on preoperative factors. For post-treatment surveillance, a combination of medical history, physical examination, carcinoembryonic antigen testing, imaging, and endoscopy is performed. Frequency depends on setting. Maximal setting recommendations are in the guideline. Additional information can be found at www.asco.org/resource-stratified-guidelines .
NOTICE: It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guidelines are intended to complement but not replace local guidelines.
Fulltext Early Detection for Colorectal Cancer: ASCO Resource-Stratified Guideline

Lopes G, Stern MC, Temin S, Sharara AI, Cervantes A, Costas-Chavarri A, et al.

J Glob Oncol, 2019 02;5:1-22.
PMID: 30802159 DOI: 10.1200/JGO.18.00213

PURPOSE: To provide resource-stratified, evidence-based recommendations on the early detection of colorectal cancer in four tiers to clinicians, patients, and caregivers.
METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational panel of medical oncology, surgical oncology, surgery, gastroenterology, health technology assessment, cancer epidemiology, pathology, radiology, radiation oncology, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (Consensus Ratings Group) for two round(s) of formal ratings.
RESULTS: Existing sets of guidelines from eight guideline developers were identified and reviewed; adapted recommendations form the evidence base. These guidelines, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of 75% or more.
CONCLUSION: In nonmaximal settings, for people who are asymptomatic, are ages 50 to 75 years, have no family history of colorectal cancer, are at average risk, and are in settings with high incidences of colorectal cancer, the following screening options are recommended: guaiac fecal occult blood test and fecal immunochemical testing (basic), flexible sigmoidoscopy (add option in limited), and colonoscopy (add option in enhanced). Optimal reflex testing strategy for persons with positive screens is as follows: endoscopy; if not available, barium enema (basic or limited). Management of polyps in enhanced is as follows: colonoscopy, polypectomy; if not suitable, then surgical resection. For workup and diagnosis of people with symptoms, physical exam with digital rectal examination, double contrast barium enema (only in basic and limited); colonoscopy; flexible sigmoidoscopy with biopsy (if contraindication to latter) or computed tomography colonography if contraindications to two endoscopies (enhanced only).
Fulltext International pooled study on diet and bladder cancer: the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics

Goossens ME, Isa F, Brinkman M, Mak D, Reulen R, Wesselius A, et al.

Arch Public Health, 2016;74:30.
PMID: 27386115 DOI: 10.1186/s13690-016-0140-1

In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7(th) most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage.
Fulltext The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

Fu YP, Kohaar I, Moore LE, Lenz P, Figueroa JD, Tang W, et al.

Cancer Res, 2014 Oct 15;74(20):5808-18.
PMID: 25320178 DOI: 10.1158/0008-5472.CAN-14-1531

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
Fulltext Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Figueroa JD, Middlebrooks CD, Banday AR, Ye Y, Garcia-Closas M, Chatterjee N, et al.

Hum Mol Genet, 2016 Mar 15;25(6):1203-14.
PMID: 26732427 DOI: 10.1093/hmg/ddv492

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
Fulltext Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Dadaev T, Saunders EJ, Newcombe PJ, Anokian E, Leongamornlert DA, Brook MN, et al.

Nat Commun, 2018 06 11;9(1):2256.
PMID: 29892050 DOI: 10.1038/s41467-018-04109-8

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
Fulltext Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.

Nat Genet, 2018 07;50(7):928-936.
PMID: 29892016 DOI: 10.1038/s41588-018-0142-8

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Schumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.

Nat Genet, 2019 02;51(2):363.
PMID: 30622367 DOI: 10.1038/s41588-018-0330-6

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
Fulltext Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.

Nat Genet, 2021 Jan;53(1):65-75.
PMID: 33398198 DOI: 10.1038/s41588-020-00748-0

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.

Nat Genet, 2021 Mar;53(3):413.
PMID: 33473200 DOI: 10.1038/s41588-021-00786-2
Fulltext Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, et al.

Nat Genet, 2023 Dec;55(12):2065-2074.
PMID: 37945903 DOI: 10.1038/s41588-023-01534-4

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.