Proportion of rare CNVs in breast cancer cases and controls.

<p>BC = breast cancer.</p>a<p>Observed only in cancer cases, or only in controls.</p>b<p>The genomic loci has annotated genes.</p>c<p>Gene disruptions include rare CNVs having breakpoints within the genes or promoter regions, and rare CNVs which delete the involved genes entirely.</p

Indication of dysfunction of <i>TP53</i> and β-estradiol centered network in the studied breast cancer cases.

<p>IPA was used to identify the connection between the genes disrupted in all cases (both familial and the cohort consisting of young breast cancer patients). The analysis identified two networks with (A) <i>TP53</i>, β-estradiol and <i>CTNNB1</i> (in green) occupying the central positions, and (B) β-estradiol (in green) occupying the central position. Genes disrupted in breast cancer cases are coloured with red. Solid lines indicate direct molecular interaction and dashed lines indicate indirect molecular interaction.</p

Examples of <i>MCPH1</i> mutation positive families (A-C).

<p>Patients with breast cancer are marked with black half circles. Other cancer types are marked with grey squares. The age at diagnosis, when known, is marked below the cancer type. Individuals genotyped for <i>MCPH1</i> c.904_916del are marked with either a plus (mutation positive) or a minus sign (mutation negative). A slashed pedigree symbol indicates a deceased individual. Triangle indicates the initially studied index patient (BR-0653, BR-0887 and BR-0154, respectively). Abbreviations: Bas: basalioma, Bt: brain tumor, Br: breast cancer, Col: colon cancer, Csu: cancer site unknown, Lar: laryngeal cancer, Ov: ovarian tumor, Pro: prostate cancer, Ut: uterine cancer, Vul: vulvar cancer.</p

Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in <i>MCPH1</i> Associating with Hereditary Breast Cancer Susceptibility

<div><p>Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, <i>MCPH1</i>, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, <i>P</i> = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, <i>P</i> = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (<i>P</i> = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (<i>P</i> = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for <i>MCHP1</i> being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.</p></div

Family history of cancers of <i>MCPH1</i> c.904_916del positive index cases^a.

<p>Family history of cancers of <i>MCPH1</i> c.904_916del positive index cases<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005816#t002fn004" target="_blank">^a</a>.</p

Occurrence of chromosomal aberrations in blood lymphocyte metaphases of heterozygous <i>MCPH1</i> c.904_916del mutation carriers and healthy controls.

<p>Occurrence of chromosomal aberrations in blood lymphocyte metaphases of heterozygous <i>MCPH1</i> c.904_916del mutation carriers and healthy controls.</p

Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among European women in BCAC, by tumor characteristic.

<p>Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among European women in BCAC, by tumor characteristic.</p

Regional plots of breast cancer association in 1p12-11.2.

<p>Regional plot of association result, recombination hotspots and linkage disequilibrium for the 1p12-11.2:120,505,799–121,481,132 breast cancer susceptibility loci. Association result from a trend test in—log10<i>P</i>values (y axis, left; red diamond, the top ranked breast cancer associated locus in the region; blue diamond, best conditioned analysis results conditioned on rs11249433; black diamonds, genotyped SNPs; gray diamonds, imputed SNPs) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on the 1000 Genomes CEU data (n = 85) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software based on the background recombination rates inferred by PHASE v2.1. Physical locations are based on hg19. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.</p

Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among women in BCAC, by ancestry.

<p>Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among women in BCAC, by ancestry.</p