The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling ...in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.
Breast cancer is the most common female cancer in the world. Numerous studies have shown that the risk of metastatic disease increases with tumor volume. In this context, it is useful to assess ...whether the regular practice of formal breast self-examination (BSE) as opposed to breast awareness has an impact on the number of cancers diagnosed, their stage, the treatments used and mortality.
The Commission of Senology (CS) of the Collège National de Gynécologie et Obstétrique Français (CNGOF) respected and followed the Grading of Recommendations Assessment, Development and Evaluation method to assess the quality of the evidence on which the recommendations were based.
The CS studied 16 questions individualizing four groups of women (general population, women aged over 75, high-risk women, and women previously treated for breast cancer). For each situation, it was determined whether the practice of BSE versus abstention from this examination led to detection of more breast cancers and/or recurrences and/or reduced treatment and/or increased survival.
BSE should not be recommended for women in the general population, who otherwise benefit from clinical breast examination by practitioners from the age of 25, and from organized screening from 50 to 74 (strong recommendation). In the absence of data on the benefits of BSE in patients aged over 75, for those at high risk and those previously treated for breast cancer, the CS was unable to issue recommendations. Thus, if women in these categories wish to undergo BSE, information on the benefits and risks observed in the general population must be given, notably that BSE is associated with a higher number of referrals, biopsies, and a reduced quality of life.
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•Impact of breast self-examination (BSE) on breast cancer (BC) early diagnosis and mortality in 4 groups: general population, women over the age of 75, at high-risk, and BC survivors.•In the absence of impact on BC mortality and early diagnosis, BSE is not recommended for general population.•BSE can lead to unnecessary biopsies, false reassurance, and finally decrease quality of life.•the absence of conclusive BSE data for the 3 other groups, no recommendations have been proposed.
Single‐nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome‐wide association studies involving mostly unselected population‐based case‐control ...series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC‐prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP‐level analysis using index cases and controls, we performed pedigree‐based association tests to capture transmission information in the sibships. We also performed gene‐ and pathway‐level analyses to maximize the power to detect associations with lower‐frequency SNPs or those with modest effect sizes. While SNP‐level analyses identified 18 loci, gene‐level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the “index case‐control” analysis, we built pathway‐derived polygenic risk scores (PRS) and assessed their performance in the population‐based CECILE study and in a data set composed of GENESIS‐affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP‐level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.
What's new?
Genetic studies have identified more than 180 single‐nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, but these studies are reaching their limits. Here, the authors evaluated SNPs in the iCOGS genotyping array using a multilevel approach, including single variant, gene, and pathway analyses. They measured the contribution of the SNPs to breast cancer in patients who have a sister with breast cancer but do not carry a BRCA1/2 mutation. They showed that a pathway‐derived polygenic risk score performed poorly in the general population, and that the best predictive model must include family history.
Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect ...modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation.
We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC.
Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure.
Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. ACC caused by a BRCA2 mutation has never been ...reported.
Nucleotide sequencing of BRCA2 in lymphocyte and tumoral DNA of a 50-year-old male who presented with an androgen-secreting ACC and a strong family history of breast, ovarian, and pancreatic cancers.
A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected. Only the BRCA2 deleted allele was retained in the ACC tumoral DNA compared with the control DNA supporting a loss of heterozygosity in the tumor.
This is the first reported case of a patient with ACC associated with a BRCA2 germline mutation. Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation.
Identifying a strategy that would optimize both the communication and understanding of the individual breast cancer risk remains a considerable challenge. This study explored the preferences of women ...with a family history of breast cancer about six presentation formats of individual breast cancer risk, as calculated from a risk prediction model. Thirty-four unaffected women attending genetic counseling because of a family history of breast cancer participated in six focus groups conducted in Québec City (2), Montréal (2) and Toronto (2), Canada. Six risk formats were presented for a fictitious case involving a 35-year-old woman (1-numerical: cumulative risk probabilities by age until 80 years; 2-risk curves: probabilities expressed in a risk curve that also provided a risk curve for a woman with no family history in first-degree relatives; 3-relative risk of breast cancer by age 80 years; 4 and 5-absolute risk of breast cancer and absolute chance of not developing breast cancer in the next 20 years; 6-qualitative: color-coded figure). Participants were asked to indicate their appreciation of each format. A group discussion followed during which participants commented on each format. The most and least appreciated formats were risk curves and relative risk, respectively. Overall, participants advocated the use of formats that combine quantitative, qualitative and visual features. Using a combination of approaches to communicate individual breast cancer risks could be associated with higher satisfaction of counselees. Given the increasing use of risk prediction models, it may be relevant to consider the preferences of both the counselee and the professional.
ObjectifsLe cancer du sein est le cancer le plus fréquent de la femme dans la plupart des pays du monde. En France, plus de 60 000 nouveaux cas sont actuellement diagnostiqués et environ 12 000 décès ...lui sont attribués annuellement. De nombreux travaux ont montré que le risque métastatique croît avec l’augmentation du volume de la tumeur. Dans ce contexte, il est utile d’évaluer si la pratique régulière de l’auto-examen des seins (AES) a un impact sur le nombre de cancers diagnostiqués, leur stade, les traitements utilisés et la mortalité.ConceptionL’élaboration de ces recommandations par la Commission de sénologie (CS) du CNGOF n’a bénéficié d’aucun financement extérieur. La méthode GRADE (Grading of Recommendations Assessment, Development and Evaluation) a été utilisée pour évaluer la qualité des données factuelles sur lesquelles ont été fondées ces recommandations.MéthodesLa CS a étudié 16 questions concernant l’AES, en individualisant quatre groupes de femmes (population générale, femmes de plus de 75 ans, femmes à haut risque, femmes antérieurement traitées pour un cancer du sein). Pour chaque situation, il a été déterminé si la pratique d’un AES comparée à l’abstention de cet examen permettait de détecter plus de cancers du sein, de récidives, de diminuer les traitements ou d’augmenter la survie.RésultatsL’AES n’est pas recommandé pour les femmes de la population générale, qui bénéficient par ailleurs d’un examen clinique des seins (par le médecin traitant ou le gynécologue) à partir de l’âge de 25 ans et d’un dépistage organisé de 50 à 74 ans (recommandation forte). En l’absence de données sur la place de l’AES chez les patientes âgées de plus de 75 ans, celles à haut risque de cancer du sein, et celles antérieurement traitées pour cancer du sein, la CS n’a pas pu émettre de recommandation. Si des femmes appartenant à ces dernières catégories souhaitent pratiquer l’AES, il faut qu’elles bénéficient d’un apprentissage rigoureux de sa technique et d’une information sur les bénéfices et risques de cette pratique observés chez les femmes de la population générale. La CS invite toutes les femmes qui détectent un changement ou une anomalie dans leurs seins à consulter sans retard un professionnel de santé.ConclusionL’AES n’est pas recommandé pour les femmes de la population générale. Aucune recommandation ne peut être émise chez les femmes âgées de plus de 75 ans, celles à haut risque de cancer du sein et celles antérieurement traitées pour un cancer du sein.
Mutations in BRCA1/2 confer a high risk of breast cancer, but literature values of this risk vary. A genotype-phenotype correlation has been found in both genes, and the effect of reproductive ...factors differs according to mutation location. Therefore, we hypothesize that such a variation may exist for other factors related to estrogen exposure.
We used a weighted Cox regression model to assess variation in breast cancer risk with these factors using location of mutation in homogeneous breast cancer risk region of BRCA1/2 in the GENEPSO study.
We found that late age at menarche reduced breast cancer risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 65% and 73%, respectively). Among premenopausal women, overweight was associated with a 45% decrease in risk whereas underweight was associated with an increased risk (HR, 2.40). A natural menopause, mainly after age 50, was associated with a high breast cancer risk (HR, 2.46), and a significant interaction between menopause status and the location of mutations was found leading up to 10% variation in absolute risk according to the age at menopause.
As observed in the general population, a late menarche, a long or a short menstrual cycle, over- or underweight, and being postmenopausal were associated with breast cancer risk in BRCA1/2 carriers. The association with the menopause was observed only when the mutation was located in the "high-risk" zones.
Taking into account modifier factors, location of mutation might be important for the clinical management of BRCA1/2 mutation carriers.
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