Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Peer reviewe

Spectrum of MECP2 mutations in Indian females with Rett Syndrome - a large cohort study

Aim: This study aimed to characterize MECP2 gene variants in Indian female patients with classical Rett syndrome (RTT).Methods: Seventy-two patients fulfilling the revised diagnostic criteria of classical RTT were enrolled and exons 2-4 of MECP2 gene were analyzed by Sanger sequencing followed by quantitative analysis using MLPA. Bioinformatic analysis was done using different software packages to predict the effect of sequence variations on the function of the MeCP2 protein.Results: A heterogeneous spectrum of MECP2 sequence variants including 13 novel variants was identified with a detection rate of 98.6%. The majority of the variants were distributed in the functional domain of MECP2 with most missense variants clustered in methyl binding domain and truncating variants in interdomain and transcription repression domain of MECP2. Genotype-phenotype correlations revealed that patients carrying early truncating variants presented with a more severe phenotype.Conclusion: RTT is a childhood neurodevelopmental disorder primarily affecting females. It is caused by mutations in the Methyl-CpG-Binding Protein 2 gene (MECP2 ), an important regulator of gene expression, located at Xq28. Variants in MECP2 can be identified in 95%-97% of individuals with Classical RTT using a combination of molecular techniques. This large cohort study from India showed the highest detection rate of MECP2 variants in classical RTT patients, emphasizing the importance of using diagnostic criteria and having a multidisciplinary team in the assessment of RTT patients, which can further help provide diagnostic testing, genetic counseling, and prenatal testing

The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position?

Genome Instability and Cance