The utility of DNA extracted from saliva for genome-wide molecular research platforms.

Objective: The study aimed to investigate the suitability of DNA extracted from saliva for high throughput molecular genotyping and DNA methylation platforms by comparing its performance with that of DNA extracted from blood. The genome-wide methylation profile, using the Infinium HumanMethylation450 Beadchip array (Illumina, San Diego, CA), was measured for 20 DNA samples. Common genetic variation was measured, using the Infinium HumanCore Beadchip (Illumina, San Diego, CA) for 4 samples (matching samples from 2 people).

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed.

Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths).

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

Background/objectives: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time.

Subjects/methods: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls.

- a novel candidate breast cancer susceptibility locus on 6q14.1.

Most non- breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.

Mammographic density and risk of breast cancer by tumor characteristics: a case-control study.

Background: In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI.

Body mass index and breast cancer survival: a Mendelian randomization analysis.

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL.

Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls.

DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies.

The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers.

Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1.

Background: Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC).

Methods: We identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases diagnosed in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis.

Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.

Background: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.

Methods: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC).

Causes of blood methylomic variation for middle-aged women measured by the HumanMethylation450 array.

To address the limitations in current classic twin/family research on the genetic and/or environmental causes of human methylomic variation, we measured blood DNA methylation for 479 women (mean age 56 years) including 66 monozygotic (MZ), 66 dizygotic (DZ) twin pairs and 215 sisters of twins, and 11 random technical duplicates using the HumanMethylation450 array. For each methylation site, we estimated the correlation for pairs of duplicates, MZ twins, DZ twins, and siblings, fitted variance component models by assuming the variation is explained by genetic factors, by shared and individual environmental factors, and by independent measurement error, and assessed the best fitting model. We found that the average (standard deviation) correlations for duplicate, MZ, DZ, and sibling pairs were 0.

Association analysis identifies 65 new breast cancer risk loci.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry.

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 with ten variants at nine new loci.

Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine.

Loss-of-function germline mutations in the PALB2 gene are associated with an increase of breast cancer risk. The purpose of this study was to characterise the spectrum of PALB2 mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of PALB2 in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123).

Association of DNA Methylation-Based Biological Age With Health Risk Factors and Overall and Cause-Specific Mortality.

Measures of biological age based on blood DNA methylation, referred to as age acceleration (AA), have been developed. We examined whether AA was associated with health risk factors and overall and cause-specific mortality. At baseline (1990-1994), blood samples were drawn from 2,818 participants in the Melbourne Collaborative Cohort Study (Melbourne, Victoria, Australia).

Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype.

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-1994) and wave 2 (2003-2007).

Twin birth changes DNA methylation of subsequent siblings.

We asked if twin birth influences the DNA methylation of subsequent siblings. We measured whole blood methylation using the HumanMethylation450 array for siblings from two twin and family studies in Australia and Korea. We compared the means and correlations in methylation between pairs of siblings born before a twin birth (BT siblings), born on either side of a twin birth (B/AT pairs) and born after a twin birth (AT siblings).

Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium.

Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.

Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.

Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium.

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind.

Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas.

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M.

Total and beverage-specific alcohol intake and the risk of aggressive prostate cancer: a case-control study.

Background: Ethanol in alcoholic beverages is a known carcinogen, but its association with aggressive prostate cancer (APC) is uncertain. Recent studies have shown a modest increase in risk of APC associated with heavy alcohol intake while association for beverage types remain inconsistent.

Methods: Using a case-control design and self-administered questionnaire, we examined the association between APC (high grade and/or advanced stage) and frequency and quantity of alcohol intake 2 years prior to enrolment.