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). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

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. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

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. Furthermore, we delineated the relationships for beverage-specific intakes of beer, red wine, white wine and spirits. RESULTS: The study included 1282 APC cases and 951 controls. Beer intake frequency of ⩾5 days per week was associated with increased risk compared with no beer intake (odds ratio=1.66, 95% confidence interval: 1.12-2.48) whereas wine was protective at all frequencies of consumption compared with those with no wine intake. For every 10 g per week ethanol intake from beer increase, the odds of advanced PC rose by 3% (OR=1.03, 95% CI: 1.02-1.05). No such increased risk was observed for red or white wine while a marginal dose-response relationship was found for spirits (OR=1.03, 95% CI: 0.99-1.07). CONCLUSIONS: Heavy beer and possibly spirits consumption is associated with increased risk while no dose-response relationship was found for red or white wine. Wine drinkers at all frequencies have a decreased risk of APC compared with those who did not drink wine.

Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens.

BACKGROUND: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. METHODS: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. RESULTS: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. CONCLUSION: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.

Multigene testing of moderate-risk genes: be mindful of the missense.

BACKGROUND: Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established. METHODS: We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold. RESULTS: Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5. CONCLUSIONS: Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

Hi-Plex targeted sequencing is effective using DNA derived from archival dried blood spots.

Many genetic epidemiology resources have collected dried blood spots (predominantly as Guthrie Cards) as an economical and efficient means of archiving sources of DNA, conferring great value to genetic screening methods that are compatible with this medium. We applied Hi-Plex to screen the breast cancer predisposition gene PALB2 in 93 Guthrie Card-derived DNA specimens previously characterized for PALB2 genetic variants via DNA derived from lymphoblastoid cell lines, whole blood, and buffy coat. Of the 93 archival Guthrie Card-derived DNAs, 92 (99%) were processed successfully and sequenced using approximately half of a MiSeq run. From these 92 DNAs, all 59 known variants were detected and no false-positive variant calls were yielded. Fully 98.13% of amplicons (5417/5520) were represented within 15-fold of the median coverage (2786 reads), and 99.98% of amplicons (5519/5520) were represented at a depth of 10 read-pairs or greater. With Hi-Plex, we show for the first time that a High-Plex amplicon-based massively parallel sequencing (MPS) system can be applied effectively to DNA prepared from dried blood spot archival specimens and, as such, can dramatically increase the scopes of both method and resource.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.

BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.

BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Tumour morphology predicts PALB2 germline mutation status.

BACKGROUND: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. METHODS: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. RESULTS: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. CONCLUSION: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.

Adult serum cytokine concentrations and the persistence of asthma.

BACKGROUND: Cytokines play a pivotal role in regulating the development and persistence of the inflammatory process in asthma. Our aim was to investigate whether asthma persistence or remission is associated with a specific cytokine profile. METHODS: The Tasmanian Longitudinal Health Study followed participants from 7 to 44 years of age. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-α) were measured at age 44 years. Participants were categorized into five phenotypes (early-onset noncurrent asthma, early-onset current asthma, late-onset noncurrent asthma and late-onset current asthma). Those who had never had asthma formed the reference group. Multivariable linear regression was used to compare serum cytokine concentrations between each phenotype and the reference group. RESULTS: IL-10 concentrations were significantly lower in serum from the early-onset current asthma group than in the reference group (ratio of geometric means 0.58; 95% confidence interval 0.33-0.99; p = 0.048). IL-6 concentrations for the late-onset remitted group were also significantly lower than in the reference group (p = 0.009). The TNF-α concentrations were significantly lower for both early-and late-onset remitted asthma phenotypes when compared with the reference group. No associations were detected between serum concentrations of IL-4, IL-5 or IL-8 and these specific longitudinal asthma phenotypes. CONCLUSION: Our findings suggest a possible role for deficient IL-10 responses in the persistence of early-onset asthma. Lower IL-6 and TNF-α concentrations in serum from those with remitted asthma suggest that these proinflammatory cytokines may be actively suppressed during asthma remission.

High and low mammographic density human breast tissues maintain histological differential in murine tissue engineering chambers.

Mammographic density (MD) is the area of breast tissue that appears radiologically white on mammography. Although high MD is a strong risk factor for breast cancer, independent of BRCA1/2 mutation status, the molecular basis of high MD and its associated breast cancer risk is poorly understood. MD studies will benefit from an animal model, where hormonal, gene and drug perturbations on MD can be measured in a preclinical context. High and low MD tissues were selectively sampled by stereotactic biopsy from operative specimens of high-risk women undergoing prophylactic mastectomy. The high and low MD tissues were transferred into separate vascularised biochambers in the groins of SCID mice. Chamber material was harvested after 6 weeks for histological analyses and immunohistochemistry for cytokeratins, vimentin and a human-specific mitochondrial antigen. Within-individual analysis was performed in replicate mice, eliminating confounding by age, body mass index and process-related factors, and comparisons were made to the parental human tissue. Maintenance of differential MD post-propagation was assessed radiographically. Immunohistochemical staining confirmed the preservation of human glandular and stromal components in the murine biochambers, with maintenance of radiographic MD differential. Propagated high MD regions had higher stromal (p = 0.0002) and lower adipose (p = 0.0006) composition, reflecting the findings in the original human breast tissue, although glands appeared small and non-complex in both high and low MD groups. No significant differences were observed in glandular area (p = 0.4) or count (p = 0.4) between high and low MD biochamber tissues. Human mammary glandular and stromal tissues were viably maintained in murine biochambers, with preservation of differential radiographic density and histological features. Our study provides a murine model for future studies into the biomolecular basis of MD as a risk factor for breast cancer.

Rare mutations in XRCC2 increase the risk of breast cancer.

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers.

Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Morphological predictors of BRCA1 germline mutations in young women with breast cancer.

BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90). CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.