Publications by authors named "John L Hopper"

809 Publications

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as "elevated microsatellite alterations at selected tetranucleotide repeats" (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for , , (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with 3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.
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http://dx.doi.org/10.3390/cancers13143529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308094PMC
July 2021

Smoking, alcohol consumption, body fatness, and risk of myelodysplastic syndromes: A prospective study.

Leuk Res 2021 Apr 24;109:106593. Epub 2021 Apr 24.

Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, 3010, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia.

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http://dx.doi.org/10.1016/j.leukres.2021.106593DOI Listing
April 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown.

Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the and genes.

Methods: Carriers of pathogenic variants of () and () genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity.

Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately.

Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 Jul 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
July 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups ( = 3.7 × 10) and young people without CRC ( = 5.8 × 10). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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http://dx.doi.org/10.3390/cancers13112589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199056PMC
May 2021

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (-2df = 1.2 × 10). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (-2df = 1.1 × 10). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
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http://dx.doi.org/10.3390/cancers13102370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156547PMC
May 2021

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

NPJ Breast Cancer 2021 May 12;7(1):52. Epub 2021 May 12.

School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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http://dx.doi.org/10.1038/s41523-021-00255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115524PMC
May 2021

Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models.

JNCI Cancer Spectr 2021 Jun 2;5(3):pkab021. Epub 2021 Mar 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study.

Methods: We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O).

Results: When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and overpredicted risk (E/O = 1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%), using the Hosmer-Lemeshow test for calibration in quantiles of risk and a 2-sided value less than.001. BOADICEA underpredicted risk (E/O = 0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); the Hosmer-Lemeshow test and a 2-sided valuewas equal to .02.

Conclusions: Although the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.
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http://dx.doi.org/10.1093/jncics/pkab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099999PMC
June 2021

Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer.

JNCI Cancer Spectr 2021 Apr 8;5(2):pkab022. Epub 2021 Mar 8.

Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Victoria, Australia.

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes-people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 , 314 , 126 , 71 , and 22 ) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided >.05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided =.51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
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http://dx.doi.org/10.1093/jncics/pkab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062848PMC
April 2021

Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case-control studies of colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869) and urothelial ( = 428) cancers, and mature B-cell lymphoma ( = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping and genes was associated with survival of overall (HR = 0.91, = 7.7 × 10) and colorectal (HR = 1.52, = 1.8 × 10) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction.
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http://dx.doi.org/10.3390/cancers13081881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070898PMC
April 2021

Enhancing Value and Uptake for Whole-Population Cohorts of Children and Parents: Methods to Integrate Registries into the Generation Victoria Cohort.

Children (Basel) 2021 Apr 7;8(4). Epub 2021 Apr 7.

Murdoch Children's Research Institute, Melbourne 3052, Australia.

Health registries are critical to understanding, benchmarking and improving quality of care for specific diseases and conditions, but face hurdles including funding, bias towards clinical rather than population samples, lack of pre-morbid and outcomes data, and absent cross-registry harmonisation and coordination. Children are particularly under-represented in registry research. This paper lays out novel principles, methods and governance to integrate diverse registries within or alongside a planned children's mega-cohort to rapidly generate translatable evidence. GenV (Generation Victoria) will approach for recruitment parents of all newborns (estimated 150,000) over two years from mid-2021 in the state of Victoria (population 6.5 million), Australia. Its sample size and population denominator mean it will contain almost all children with uncommon or co-morbid conditions as they emerge over time. By design, it will include linked datasets, biosamples (including from pregnancy), phenotypes and participant-reported measures, all of which will span pre-morbid to long-term outcomes. We provide a vignette of a planned new registry for high-risk pregnancies to illustrate the possibilities. To our knowledge, this is the first paper to describe such a methodology designed prospectively to enhance both the clinical relevance of a large multipurpose cohort and the value and inclusivity of registries in a population.
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http://dx.doi.org/10.3390/children8040285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067795PMC
April 2021

Prediagnosis alcohol intake and metachronous cancer risk in cancer survivors: A prospective cohort study.

Int J Cancer 2021 Apr 19. Epub 2021 Apr 19.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Alcohol consumption is a known cause of cancer, but its role in the etiology of second primary (metachronous) cancer is uncertain. Associations between alcohol intake up until study enrollment (prediagnosis) and risk of metachronous cancer were estimated using 9435 participants in the Melbourne Collaborative Cohort Study who were diagnosed with their first invasive cancer after enrollment (1990-1994). Follow-up was from date of first invasive cancer until diagnosis of metachronous cancer, death or censor date (February 2018), whichever came first. Alcohol intake for 10-year periods from age 20 until decade encompassing baseline using recalled beverage-specific frequency and quantity was used to calculate baseline and lifetime intakes, and group-based intake trajectories. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. After a mean follow-up of 7 years, 1512 metachronous cancers were identified. A 10 g/d increment in prediagnosis lifetime alcohol intake (HR = 1.03, 95% CI = 1.00-1.06; P = .02) and an intake of ≥60 g/d (HR = 1.32, 95% CI = 1.01-1.73) were associated with increased metachronous cancer risk. We observed positive associations (per 10 g/d increment) for metachronous colorectal (HR = 1.07, 95% CI = 1.00-1.14), upper aero-digestive tract (UADT) (HR = 1.16, 95% CI = 1.00-1.34) and kidney cancer (HR = 1.24, 95% CI = 1.10-1.39). Although these findings were partly explained by effects of smoking, the association for kidney cancer remained unchanged when current smokers or obese individuals were excluded. Alcohol intake trajectories over the life course confirmed associations with metachronous cancer risk. Prediagnosis long-term alcohol intake, and particularly heavy drinking, may increase the risk of metachronous cancer, particularly of the colorectum, UADT and kidney.
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http://dx.doi.org/10.1002/ijc.33603DOI Listing
April 2021

Residential surrounding greenness and DNA methylation: An epigenome-wide association study.

Environ Int 2021 09 13;154:106556. Epub 2021 Apr 13.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia. Electronic address:

Background: DNA methylation is a potential biological mechanism through which residential greenness affects health, but little is known about its association with greenness and whether the association could be modified by genetic background. We aimed to evaluate the association between surrounding greenness and genome-wide DNA methylation and potential gene-greenness interaction effects on DNA methylation.

Methods: We measured blood-derived DNA methylation using the HumanMethylation450 BeadChip array (Illumina) for 479 Australian women, including 66 monozygotic, 66 dizygotic twin pairs, and 215 sisters of these twins. Surrounding greenness was represented by Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) within 300, 500, 1000 or 2000 m surrounding participants' home addresses. For each cytosine-guanine dinucleotide (CpG), the associations between its methylation level and NDVI or EVI were evaluated by generalized estimating equations, after adjusting for age, education, marital status, area-level socioeconomic status, smoking behavior, cell-type proportions, and familial clustering. We used comb-p and DMRcate to identify significant differentially methylated regions (DMRs). For each significant CpG, we evaluated the interaction effects of greenness and single-nucleotide polymorphisms (SNPs) within ±1 Mb window on its methylation level.

Results: We found associations between surrounding greenness and blood DNA methylation for one CpG (cg04720477, mapped to the promoter region of CNP gene) with false discovery rate [FDR] < 0.05, and for another 9 CpGs with 0.05 ≤ FDR < 0.10. For two of these CpGs, we found 33 SNPs significantly (FDR < 0.05) modified the greenness-methylation association. There were 35 significant DMRs related to surrounding greenness that were identified by both comb-p (Sidak p-value < 0.01) and DMRcate (FDR < 0.01). Those CpGs and DMRs were mapped to genes related to many human diseases, such as mental health disorders and neoplasms as well as nutritional and metabolic diseases.

Conclusions: Surrounding greenness was associated with blood DNA methylation of many loci across human genome, and this association could be modified by genetic variations.
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http://dx.doi.org/10.1016/j.envint.2021.106556DOI Listing
September 2021

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in : Findings from the Australian Breast Cancer Family Registry.

Cancers (Basel) 2021 Mar 18;13(6). Epub 2021 Mar 18.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria 3168, Australia.

Case-control studies of breast cancer have consistently shown that pathogenic variants in are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic variants (combined) was 4.9 (95% CI 2.5-9.5) relative to non-carriers. The HR for carriers of the c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in .
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http://dx.doi.org/10.3390/cancers13061378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003064PMC
March 2021

: Genetic Variation, Heritable Methylation and Disease Association.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the gene region in multiple-case breast cancer families in which methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The -mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with methylation ( < 1.5 × 10); however, these explained little of the methylation variation (R < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence methylation. SNP-based heritability estimates were consistent with the mQTL findings (h = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at . Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable cluster.
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http://dx.doi.org/10.3390/ijms22052535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961504PMC
March 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 May 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

Age dependency of the polygenic risk score for colorectal cancer.

Am J Hum Genet 2021 03;108(3):525-526

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008484PMC
March 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223655PMC
July 2021

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants.

JAMA Oncol 2021 Apr;7(4):585-592

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

Importance: Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear.

Objective: To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants.

Design, Setting, And Participants: This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020.

Exposure: Risk-reducing salpingo-oophorectomy.

Main Outcomes And Measures: In all analyses, the primary end point was the time to a first primary breast cancer.

Results: A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO.

Conclusions And Relevance: Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.
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http://dx.doi.org/10.1001/jamaoncol.2020.7995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907985PMC
April 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies.

Int J Cancer 2021 Jun 22;148(11):2759-2773. Epub 2021 Feb 22.

Hellenic Health Foundation, Athens, Greece.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (P = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.
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http://dx.doi.org/10.1002/ijc.33504DOI Listing
June 2021

Motivators of Inappropriate Ovarian Cancer Screening: A Survey of Women and Their Clinicians.

JNCI Cancer Spectr 2021 Feb 8;5(1):pkaa110. Epub 2020 Dec 8.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: This study examined why women and doctors screen for ovarian cancer (OC) contrary to guidelines.

Methods: Surveys, based on the Theoretical Domains Framework, were sent to women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and family physicians and gynecologists who organized their screening.

Results: Of 1264 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer women, 832 (65.8%) responded. In the past 2 years, 126 (15.1%) had screened. Most of these (n = 101, 80.2%) would continue even if their doctor told them it is ineffective. For women, key OC screening motivators operated in the domains of social role and goals (staying healthy for family, 93.9%), emotion and reinforcement (peace of mind, 93.1%), and beliefs about capabilities (tests are easy to have, 91.9%). Of 531 clinicians 252 (47.5%) responded; a minority (family physicians 45.8%, gynecologists 16.7%) thought OC screening was useful. For gynecologists, the main motivators of OC screening operated in the domains of environmental context (lack of other screening options, 27.6%), and emotion (patient peace of mind, 17.2%; difficulty discontinuing screening, 13.8%). For family physicians,, the strongest motivators were in the domains of social influence (women ask for these tests, 20.7%), goals (a chance these tests will detect cancer early, 16.4%), emotion (patient peace of mind, 13.8%), and environmental context (no other OC screening options, 11.2%).

Conclusion: Reasons for OC screening are mostly patient driven. Clinician knowledge and practice are discordant. Motivators of OC screening encompass several domains, which could be targeted in interventions to reduce inappropriate OC screening.
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http://dx.doi.org/10.1093/jncics/pkaa110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853181PMC
February 2021

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome.

Am J Epidemiol 2021 02;190(2):230-238

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.
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http://dx.doi.org/10.1093/aje/kwaa175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210745PMC
February 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

Am J Obstet Gynecol 2021 07 22;225(1):51.e1-51.e17. Epub 2021 Jan 22.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Background: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.

Objective: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates.

Study Design: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use.

Results: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size.

Conclusion: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
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http://dx.doi.org/10.1016/j.ajog.2021.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278569PMC
July 2021

A streamlined model for use in clinical breast cancer risk assessment maintains predictive power and is further improved with inclusion of a polygenic risk score.

PLoS One 2021 22;16(1):e0245375. Epub 2021 Jan 22.

Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC, Australia.

Five-year absolute breast cancer risk prediction models are required to comply with national guidelines regarding risk reduction regimens. Models including the Gail model are under-utilized in the general population for various reasons, including difficulty in accurately completing some clinical fields. The purpose of this study was to determine if a streamlined risk model could be designed without substantial loss in performance. Only the clinical risk factors that were easily answered by women will be retained and combined with an objective validated polygenic risk score (PRS) to ultimately improve overall compliance with professional recommendations. We first undertook a review of a series of 2,339 Caucasian, African American and Hispanic women from the USA who underwent clinical testing. We first used deidentified test request forms to identify the clinical risk factors that were best answered by women in a clinical setting and then compared the 5-year risks for the full model and the streamlined model in this clinical series. We used OPERA analysis on previously published case-control data from 11,924 Gail model samples to determine clinical risk factors to include in a streamlined model: first degree family history and age that could then be combined with the PRS. Next, to ensure that the addition of PRS to the streamlined model was indeed beneficial, we compared risk stratification using the Streamlined model with and without PRS for the existing case-control datasets comprising 1,313 cases and 10,611 controls of African-American (n = 7421), Caucasian (n = 1155) and Hispanic (n = 3348) women, using the area under the curve to determine model performance. The improvement in risk discrimination from adding the PRS risk score to the Streamlined model was 52%, 46% and 62% for African-American, Caucasian and Hispanic women, respectively, based on changes in log OPERA. There was no statistically significant difference in mean risk scores between the Gail model plus risk PRS compared to the Streamlined model plus PRS. This study demonstrates that validated PRS can be used to streamline a clinical test for primary care practice without diminishing test performance. Importantly, by eliminating risk factors that women find hard to recall or that require obtaining medical records, this model may facilitate increased clinical adoption of 5-year risk breast cancer risk prediction test in keeping with national standards and guidelines for breast cancer risk reduction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822550PMC
June 2021

Association of variably methylated tumour DNA regions with overall survival for invasive lobular breast cancer.

Clin Epigenetics 2021 01 18;13(1):11. Epub 2021 Jan 18.

Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Background: Tumour DNA methylation profiling has shown potential to refine disease subtyping and improve the diagnosis and prognosis prediction of breast cancer. However, limited data exist regarding invasive lobular breast cancer (ILBC). Here, we investigated the genome-wide variability of DNA methylation levels across ILBC tumours and assessed the association between methylation levels at the variably methylated regions and overall survival in women with ILBC.

Methods: Tumour-enriched DNA was prepared by macrodissecting formalin-fixed paraffin embedded (FFPE) tumour tissue from 130 ILBCs diagnosed in the participants of the Melbourne Collaborative Cohort Study (MCCS). Genome-wide tumour DNA methylation was measured using the HumanMethylation 450K (HM450K) BeadChip array. Variably methylated regions (VMRs) were identified using the DMRcate package in R. Cox proportional hazards regression models were used to assess the association between methylation levels at the ten most significant VMRs and overall survival. Gene set enrichment analyses were undertaken using the web-based tool Metaspace. Replication of the VMR and survival analysis findings was examined using data retrieved from The Cancer Genome Atlas (TCGA) for 168 ILBC cases. We also examined the correlation between methylation and gene expression for the ten VMRs of interest using TCGA data.

Results: We identified 2771 VMRs (P < 10) in ILBC tumours. The ten most variably methylated clusters were predominantly located in the promoter region of the genes: ISM1, APC, TMEM101, ASCL2, NKX6, HIST3H2A/HIST3H2BB, HCG4P3, HES5, CELF2 and EFCAB4B. Higher methylation level at several of these VMRs showed an association with reduced overall survival in the MCCS. In TCGA, all associations were in the same direction, however stronger than in the MCCS. The pooled analysis of the MCCS and TCGA data showed that methylation at four of the ten genes was associated with reduced overall survival, independently of age and tumour stage; APC: Hazard Ratio (95% Confidence interval) per one-unit M-value increase: 1.18 (1.02-1.36), TMEM101: 1.23 (1.02-1.48), HCG4P3: 1.37 (1.05-1.79) and CELF2: 1.21 (1.02-1.43). A negative correlation was observed between methylation and gene expression for CELF2 (R = - 0.25, P = 0.001), but not for TMEM101 and APC.

Conclusions: Our study identified regions showing greatest variability across the ILBC tumour genome and found methylation at several genes to potentially serve as a biomarker of survival for women with ILBC.
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http://dx.doi.org/10.1186/s13148-020-00975-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814464PMC
January 2021
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