Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families.

PURPOSE: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance due to an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. METHODS: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10.000 person years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onwards. Attained-age analyses were performed for sites in which significant increased risks were found. Considering study design, we primarily focused on cancer risk in women. RESULTS: We found significant increased risks of colorectal cancer (CRC; SIR=1.43, 95%CI=1.14-1.76; AER=1.43) and hematological cancers (SIR=1.32; 95%CI=1.02-1.67; AER=0.87). CRC was significantly more frequent from age 45 onwards. CONCLUSION: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well, however, further research is needed to determine who may profit from this additional colorectal surveillance.

Long-term outcome of high-grade serous carcinoma established in risk-reducing salpingo-oophorectomy specimens in asymptomatic BRCA1/2 germline pathogenic variant carriers.

OBJECTIVE: The aim of this study was to describe the long-term outcome of asymptomatic BRCA1/2 germline pathogenic variant (GPV) carriers with high-grade serous carcinoma (HGSC) in their risk-reducing salpingo-oophorectomy (RRSO) specimen. METHODS: In a previously described cohort of asymptomatic BRCA1/2 GPV carriers derived from the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) study, women with HGSC at RRSO were identified. Main outcome was ten-year disease-free survival (DFS). Secondary outcomes were time to recurrence, ten-year disease-specific survival (DSS), ten-year overall survival (OS). Patient, disease and treatment characteristics associated with recurrence were described. RESULTS: The 28 included women with HGSC at RRSO were diagnosed at a median age of 55.3 years (range: 33.5-74.3). After staging, eighteen women had (FIGO) stage I, three stage II and five had stage III disease. Two women did not undergo surgical staging and were classified as unknown stage. After a median follow-up of 13.5 years (range: 9.1-24.7), six women with stage I (33%), one woman with stage II (33%), two women with stage III (40%) and none of the women with unknown stage developed a recurrence. Median time to recurrence was 6.9 years (range: 0.8-9.2 years). Ten-year DFS was 68%, ten-year DSS was 88% and ten-year OS was 82%. CONCLUSION: Most asymptomatic BRCA1/2 GPV carriers with HGSC at RRSO were diagnosed at an early stage. Nevertheless, after a median follow-up of 13.5 years, nine of the 28 women with HGSC at RRSO developed a recurrence after a median of 6.9 years.

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families.

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

Breast cancer genomes from CHEK2 c.1100delC mutation carriers lack somatic TP53 mutations and display a unique structural variant size distribution profile.

BACKGROUND: CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. METHODS: We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER- and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. RESULTS: BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. CONCLUSIONS: CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.

Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on cognition in women with high familial risk of ovarian cancer: A cross-sectional study.

OBJECTIVE: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. DESIGN: A cross-sectional study with prospective follow-up, nested in a nationwide cohort. SETTING: Multicentre in the Netherlands. POPULATION OR SAMPLE: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment. METHODS: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. MAIN OUTCOME MEASURES: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO. RESULTS: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). CONCLUSIONS: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Sexual functioning more than 15 years after premenopausal risk-reducing salpingo-oophorectomy.

BACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown. OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy. STUDY DESIGN: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years. CONCLUSION: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity.

Breast cancer risks associated with missense variants in breast cancer susceptibility genes.

BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Rare germline copy number variants (CNVs) and breast cancer risk.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

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.

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) 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 PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 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 PRS313, 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 PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

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

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Endometrial Cancer Risk in Women With Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.

BACKGROUND: Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study. METHODS: We selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided. RESULTS: Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). CONCLUSIONS: BRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

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

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 < 10-8, 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.

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

[Congenital heart block revealing a maternal systemic disease : pathophysiology and therapeutic approaches]. / Bloc auriculoventriculaire congénital révélateur d'une pathologie maternelle systémique : physiopathologie et approches thérapeutiques.

Immunologic congenital atrioventricular block is due to the presence of anti-SSA and anti-SSB antibodies in maternal blood. This pathology is often diagnosed when the status is irreversible and is consequently associated with a high morbi-mortality. Close monitoring for high risk pregnancies can help to diagnose first and second degrees heart block and treatments can be offered when the block is still reversible. Fluorocorticoids, betamimetics and hydroxychloroquine use is not consensual. Studies are still in progress to prove their utility. We report the antenatal managing of a patient in which Goujerot-Sjögren disease was diagnosed after the revealing of an atrioventricular block in her fetus. After a brief physiopathological description, we present the current knowledge in preventive and curative treatments.

Le bloc auriculoventriculaire congénital d'origine immunologique est lié à la présence dans le sang maternel d'anticorps anti-SSA et anti-SSB. Le diagnostic est le plus souvent posé à un stade irréversible et est alors associé à une morbi-mortalité importante. La surveillance rapprochée des grossesses à risque permet de diagnostiquer des blocs de premier et deuxième degré et de proposer des traitements à un stade réversible de la maladie. L'utilisation de corticoïdes fluorés, de bêtamimétiques et de l'hydroxychloroquine n'est pas consensuelle. Des études sont toujours en cours pour valider leur utilité. Nous rapportons la prise en charge anténatale d'une patiente chez qui le diagnostic de syndrome de Goujerot-Sjögren a été posé suite à la découverte d'un bloc auriculoventriculaire chez son fœtus. Après un bref rappel physiopathologique, nous exposons l'état actuel des connaissances en ce qui concerne les traitements préventifs et curatifs.

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

Molecular determination of the clonal relationships between multiple tumors in BRCA1/2-associated breast and/or ovarian cancer patients is clinically relevant.

Female BRCA1/2 mutation carriers affected with breast and/or ovarian cancer may develop new tumor deposits over time. It is of utmost importance to know the clonal relationships between multiple tumor localizations, enabling differentiation between multiple primaries or metastatic disease with consequences for therapy and prognosis. We evaluated the value of targeted next generation sequencing in the diagnostic workup of BRCA1/2 mutation carriers with ≥2 tumor localizations and uncertain tumor origins. Forty-two female BRCA1/2 mutation carriers with ≥2 tumor localizations were selected. Patients with inconclusive tumor origin after histopathological revision were 'cases'; patients with certain tumor origin of ≥3 tumors served as 'controls'. Tumors of cases and controls were analyzed by targeted next generation sequencing using a panel including CDKN2A, PTEN and TP53, hotspot mutation sites for 27 different genes and 143 single nucleotide polymorphisms for detection of loss of heterozygosity. Based on prevalence of identical or different mutations and/or loss of heterozygosity patterns, tumors were classified as 'multiple primaries' or 'one entity'. Conventional histopathology yielded a conclusive result in 38/42 (90%) of patients. Four cases and 10 controls were analyzed by next generation sequencing. In 44 tumor samples, 48 mutations were found; 39 (81%) concerned TP53 mutations. In all 4 cases, the intra-patient clonal relationships between the tumor localizations could be unequivocally identified by molecular analysis. In all controls, molecular outcomes matched the conventional histopathological results. In most BRCA1/2 mutation carriers with multiple tumors routine pathology work-up is sufficient to determine tumor origins and relatedness. In case of inconclusive conventional pathology results, molecular analyses using next generation sequencing can reliably determine clonal relationships between tumors, enabling optimal treatment of individual patients.