Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers

The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry

<div><p>The Bene Israel Jewish community from West India is a unique population whose history before the 18^th century remains largely unknown. Bene Israel members consider themselves as descendants of Jews, yet the identity of Jewish ancestors and their arrival time to India are unknown, with speculations on arrival time varying between the 8th century BCE and the 6th century CE. Here, we characterize the genetic history of Bene Israel by collecting and genotyping 18 Bene Israel individuals. Combining with 486 individuals from 41 other Jewish, Indian and Pakistani populations, and additional individuals from worldwide populations, we conducted comprehensive genome-wide analyses based on F_ST, principal component analysis, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing and allele sharing autocorrelation decay, as well as contrasted patterns between the X chromosome and the autosomes. The genetics of Bene Israel individuals resemble local Indian populations, while at the same time constituting a clearly separated and unique population in India. They are unique among Indian and Pakistani populations we analyzed in sharing considerable genetic ancestry with other Jewish populations. Putting together the results from all analyses point to Bene Israel being an admixed population with both Jewish and Indian ancestry, with the genetic contribution of each of these ancestral populations being substantial. The admixture took place in the last millennium, about 19–33 generations ago. It involved Middle-Eastern Jews and was sex-biased, with more male Jewish and local female contribution. It was followed by a population bottleneck and high endogamy, which can lead to increased prevalence of recessive diseases in this population. This study provides an example of how genetic analysis advances our knowledge of human history in cases where other disciplines lack the relevant data to do so.</p></div

ADMIXTURE analysis for Jewish, Indian, Pakistani, Middle Eastern (Druze, Bedouin and Palestinians) and representative HapMap (CEU, YRI, JPT and CHB) populations.

<p>K, the number of clusters, varies from K = 3 to K = 8. We colored some of the populations names based on the following groups: Bene Israel (purple), Jews (red), Indian (blue) and Middle-Eastern (green). See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s003" target="_blank">S3 Fig</a>.</p

Founder events in Bene Israel population.

<p>(A) Total lengths of runs of homozygosity (ROH) in Jewish, Indian and HapMap populations. The larger variance in ROH values in some Indian populations is due to smaller sample size. (B-C) Autocorrelation in Bene Israel pairs, as a function of the genetic distance, after subtracting the autocorrelation between Bene Israel and other (B) Jewish and (C) Indian populations. Blue and red lines correspond to the fitted curve based on a single and two founder events, respectively.</p

IBD sharing between and within Jewish, Indian, Pakistani and Middle-Eastern populations.

<p>(A) Average IBD sharing between different populations. For each population we measured its average IBD with Bene Israel (purple) and all other Jewish (red) and Indian (blue) populations. (B) IBD sharing of Bene Israel with other Jewish and Indian populations. (C) Average IBD sharing between different populations. For each population from panel A, with the addition of Pakistani and Middle-Eastern populations, we measured its average IBD with Bene Israel (purple) and all other Jewish (red) and Indian (blue) populations. (D) IBD sharing of Bene Israel with other Jewish, Indian, Pakistani and non-Jewish Middle-Eastern populations. Analyses in panels C-D were performed on the dataset merged with HGDP dataset that contained smaller number of SNPs, and therefore the differences in IBD sharing values. (E) IBD sharing <i>within</i> populations.</p

Principal Component Analysis of Jewish, Indian and worldwide populations.

<p>Each panel presents the top two principal components for a set of populations that include Bene Israel together with: (A) Jewish, Indian, Pakistani, Middle Eastern and four worldwide HapMap populations (CEU, CHB, JPT and YRI); (B) Jewish, Middle-Eastern, Pakistani and Indian populations; (C) Indian and Pakistani populations; (D) Jewish, Middle-Eastern and Pakistani populations. Abbreviations of Jewish populations: Bene Israel (Bene), Algerian Jews (ALGJ), Ashkenazi Jews (ASHJ), Djerban Jews (DJEJ), Georgian Jews (GEOJ), Greek Jews (GRKJ), Iranian Jews (IRNJ), Iraqi Jews (IRQJ), Italian Jews (ITAJ), Libyan Jews (LIBJ), Moroccan Jews (MORJ), Syrian Jews (SYRJ), Tunisian Jews (TUNJ), Yemenite Jews (YMNJ).</p

Bene Israel as an admixed population with Indian and Jewish ancestry.

<p>(A) Bene Israel as an admixed population of Indian and Jewish origin. Admixture time (~19–33 generations ago) is after the ANI-ASI admixture of Indian populations (64–144 generations ago). The ANI side is associated with Eurasian populations while ASI is associated with indigenous Andaman Island people (e.g., Onge). Dotted lines correspond to admixture between populations. This is a schematic overview of Bene Israel genetic history and branch lengths are not proportional to actual time. (B) ALDER admixture proportions estimations for Indian and Jewish populations being ancestral populations of the Bene Israel community. Values (with standard errors) are based on ALDER analysis with one-reference population. See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s016" target="_blank">S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s017" target="_blank">S3</a> Tables. (C) GLOBETROTTER estimations for Indian (55%) and Jewish (45%) clusters proportions in Bene Israel admixture. The contribution of each population in each cluster is also presented.</p

Autosome to chromosome X genetic drift ratio between Bene Israel and other populations.

<p>The line represents the 3/4 ratio expected under the null hypothesis of similar demography of males and females in respect to the other populations examined (Jews and Indians, in our case). See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s019" target="_blank">S5 Table</a>.</p