Geomorphological Processes Associated with an Ice-Marginal Lake at Bridge Glacier, British Colombia

Four well-defined strandlines mark the former extent and drawdown phases of an ice-marginal lake that was impounded by Bridge Glacier during the Little Ice Age. 14C dates, tree-ring counts and historic air photographs indicate that the lake stood at the highest strandline (L1) for about 550 years, and at the lower strandlines for only a few decades in total. Estimates of rates for geomorphic processes are based on absolute chronology, ground measurements and photogrammetry: benches along L1 may have been cut into bedrock and till at rates of about 3.6 and 7.3 cm yr~1 respectively; a spillway channel was incised into a lateral moraine at 2.2 m yr\ and mean bedload transport to a delta from a 6.25 km2 ice-covered sub-basin was about 945 m3 yr '. Major floods from the stable, rock-cut spillway of the highest lake, that may have been caused by temporary damming of the lake outlet by snowbanks or lake ice, constructed a large fan on the main Bridge Glacier outwash apron. The lower lakes probably drained catastrophically due to failure of moraine and ice dams, but the resulting floods were rapidly attenuated downstream.Quatre lignes de rivage bien définies montrent l'étendue d'un lac juxta-glaciaire retenu par le glacier Bridge pendant le Petit Âge glaciaire. Des datations au radiocarbone, des comptages de cernes annuels et l'analyse d'anciennes photos aériennes démontrent que le lac s'est maintenu au niveau correspondant à la plus haute ligne de rivage (L1) pendant environ 550 ans, et aux niveaux inférieurs pendant tout au plus quelques décennies. Les vitesses associées aux processus géomorphologiques sont fondées sur la chronologie absolue, les levés de terrain et la photogrammétrie. Les banquettes le long du rivage L1 ont peut-être été entaillées dans la roche et le till à des taux d'environ 3,6 et 7,3 cm a-1 respectivement; un chenal déversoir a incisé la moraine latérale à une vitesse de 2,2 m a-1 et le transport de la charge de fond provenant d'un sous-bassin englacé de 6,45 km2 vers un delta s'est fait à une vitesse moyenne d'environ 945 m3 a-1. Des crues majeures débouchant du chenal déversoir associé au niveau lacustre supérieur ont construit un grand cône alluvial sur la principale plaine d'épandage fluvioglaciaire. Ces crues ont probablement été causées par les endiguements temporaires de l'exutoire par des congères ou des embâcles. Les lacs des niveaux inférieurs se sont probablement vidangés de façon brutale en raison de la rupture des barrages morainiques ou glaciaires, mais les crues qui en ont résulté ont vite été atténuées en aval.Vier klar abgegrenzte Uferlinien markieren die ehemalige Ausdehnung und die Rùckzugsphasen eines glazialen Randsees, der wàhrend der Kleinen Eiszeit durch den Bridge-Gletscher eingesperrt war. 14C-Daten, dendrochronologische Zàhlungen und historische Luftaufnahmen zeigen, dass der See ungefàhr 550 Jahre lang die hochste Uferlinie einnahm (L1) und insgesamt nur einige Jahrzehnte lang die niedrigeren Uferlinien. Die Schàtzungen der Geschwindigkeit der geomorphologischen Prozesse stûtzen sich auf die absolute Chronologie, Bodenabmes-sungen und Photogrammétrie: Leisten entlang L1 sind wahrscheinlich in anstehendes Gestein und Till mit einer Rate von etwa 3,6 bzw. 7,3 cm Jahr1 eingeschnitten worden; ein Ablasskanal wurde in eine seitliche Moràne mit einer Geschwindigkeit von 2,2 m Jahr' eingeschnitten, und der durchschnittliche Transport der Sedimentfracht von einem 6,25 km2 grossen eisbedeckten Unterbecken zu einem Delta war etwa 945 m3 Jahr-1. Grôssere Hochfluten von dem festen in den FeIs geschnittenen Ablasskanal des hôchstgelegenen Sees, die môglicherweise durch vorùbergehende Eindâmmung des See-Ausflusses durch Schneebânke oder Seeeis bewirkt wurden, formten einen breiten Alluvialfâcher auf der glazialen Haupt-schwemmebene des Bridge-Gletschers. Die niedriger gelegenen Seen haben sich wahrscheinlich katastrophenartig geleert aufgrund des Zusammenbruchs von Morânenund Eisdâmmen, doch wurden die entstandenen Fluten stromabwàrts schnell gemildert

The Cordilleran Ice Sheet in Northern British Colombia

Dates from lavas associated with tills and erratics indicate that ice-sheet glaciations occurred between 4 and 0.6 Ma BP. The few radiocarbon dates that are available suggest that the chronology of the Late Wisconsinan (Fraser Glaciation) ice sheet of northern British Columbia was similar to that of the southern part of the province. During what may have been a long, early phase of this glaciation, Glacial Lake Stikine was dammed by advancing valley glaciers in the Coast Mountains, and alpine glaciers developed on the intermontane plateau. At the climax of Fraser Glaciation, ice-flow patterns were dominated by outflow from a névé centred over the northern Skeena Mountains. Déglaciation occurred partly by frontal retreat of ice tongues and partly by downwasting of stagnant ice. Recessional moraines mark one or more resurgences or stillstands of the ice margin. During déglaciation, Stikine River valley was occupied by an active outlet glacier and a major subglacial drainage system.Les dates recueillies sur les laves associées aux tills et aux erratiques montrent que des glaciations de grande envergure se sont manifestées entre 4 et 0,6 Ma BP. Les quelques datations au radiocarbone disponibles indiquent que la chronologie de l'inlandsis du Wisconsinien supérieur (Glaciation de Fraser) était semblable au nord comme au sud de la Colombie-Britannique. Au cours de ia longue phase initiale de la glaciation, le Lac Stikine était endigué par l'avancée de glaciers de vallée de la chaîne Côtière et par des glaciers alpins en provenance du plateau intermontagnard. À l'optimum de la Glaciation de Fraser, le réseau d'écoulement glaciaire était dominé par l'écoulement à partir d'un névé centré sur le nord des monts Skeena. La déglaciation s'est faite en partie par le retrait de langues glaciaires et en partie par la fonte de glace stagnante. Les moraines de retrait montrent qu'il y a eu une ou plusieurs récurrences ou haltes de la marge glaciaire. Pendant la déglaciation, (a vallée de la Stikine River était occupée par un glacier de décharge actif et un réseau de drainage sous-glaciaire important.Daten von Laven, die in Verbindung mit Grundmorânen und erratischen Blôcken gebracht werden, zeigen, dass es zwischen 4 und 0.6 Ma v.u.Z zu Eisdecke-Vereisungen gekommen ist. Die wenigen zur Verfùgung stehenden Radiokarbondaten legen nahe, dass die Chronologie der spâtwisconsinischen (Fraser-Vereisung) Eisdecke im Norden von British Columbia derjenigen des sûdlichen Teils der Provinz àhnlich war. Wâhrend einer Période, die eine lange, frùhe Phase dieser Vereisung gewesen sein kônnte, war der glaziale See Stikine durch in den Kùstenbergen vorrùckende Talgletscher gestaut, und alpine Gletscher entwickelten sich auf dem Plateau zwischen den Bergen. Wâhrend des Hôhepunkts der Fraser-Vereisung wurden die Eisstrômungsmuster durch den Ausfiuss von einem Firnfeld mitten ùber den nôrdlichen Skeena-Bergen beherrscht. Die Enteisung geschah teilweise durch frontalen Rùckzug der Eiszungen und teilweise durch Abzehrung von stagnierendem Eis. Rùckzugsmorânen markieren eine oder mehrere Rùckvorstôsse oder einen Stillstand des Eisrands. Wâhrend der Enteisung befand sich im Stikine-Flusstal ein Gletscher mit aktivem Austritt und einem bedeutenden subglazialen Drânage-System

The Cordilleran Ice Sheet and the Glacial Geomorphology of Southern and Central British Colombia

This paper reviews the current state of knowledge about the Cordilleran Ice Sheet in southern and central British Columbia. Reconstructions of the ice sheet and the styles of ice expansion and déglaciation are based on extensive and varied glacigenic sediments and landforms that date from Late Wisconsinan (Fraser) Glaciation. Late-glacial lakes and sea level changes are also described and related to isostatic and eustatic effects. The timing of ice expansion and recession during Fraser Glaciation was markedly asymmetric: ice build-up commenced about 29 000 years BP, culminated between 14 500 and 14 000 years BP1 and déglaciation was largely completed by 11 500 years BP. Most of this interval appears to have been dominated by montane glaciation, which produced striking erosional landforms. A Cordilleran Ice Sheet existed from only about 19 000 to 13 500 years BP. An older glaciation, probably of Early Wisconsinan age, has been recognized from widespread exposures of drift that underlies Middle Wisconsinan non-glacial sediments. Pre-Wisconsinan drift is present near Vancouver. Drifts of late Tertiary to Middle Pleistocene age have been dated by association with volcanic sequences in the southern Coast Mountains and the central Interior, and by paleomagnetic studies in the southern Interior.On résume ici l'état des connaissances sur l'Inlandsis de la Cordillère du sud et du centre de la Colombie-Britannique. Les reconstitutions de l'inlandsis et les modes d'englaciation et de déglaciation sont fondés sur les formes et les sédiments glaciaires qui datent de la glaciation du Wisconsinien supérieur (Fraser). On décrit également les lacs tardiglaciaires et les changements du niveau marin en relation avec les conséquences sur les niveaux isostatique et eustatique. Les rythmes de la progression et du retrait glaciaire ont été tout à fait différents; la giaciation a commencé vers 29 000 BP, a connu son optimum entre 14 500 et 14 000 BP et la déglaciation était à toutes fins utiles terminée dès 11 500 BP. La plus grande partie de cette époque a été dominée par une glaciation de type alpin, qui a engendré des formes d'érosion remarquables. L'Inlandsis de la Cordillère n'a existé que de 19 000 à 13 500 BP. On a identifié une glaciation plus ancienne, probablement du Wisconsinien inférieur, à partir des affleurements répandus de dépôts glaciaires sous-jacents aux sédiments non glaciaires du Wisconsinien moyen. On a observé des dépôts glaciaires pré-wisconsiniens près de Vancouver. Les dépôts glaciaires datant du Tertiaire supérieur au Pleistocene moyen ont été datés par association aux séquences volcaniques du sud des montagnes Côtières et du centre de l'Intérieur et grâce à des études de paléomagnétisme menées dans le sud du système de l'Intérieur.Dieser Artikel gibt einen uberblick ûber den gegenwartigen Forschungsstand zur Kordilleren-Eisdecke im Sùden und im Zentrum von British Columbia. Die Rekonstruktionen der Eisdecke und der Art und Weise der Eisausdehnung und Enteisung stùtzen sich auf extensive und mannigfache glazigene Sedimente und Landformen, die aus der Spât-Wisconsin- (Fraser) Vereisung stammen. Spàtglaziale Seen und Meeresniveauwechsel werden auch beschrieben und in Beziehung zu isostatischen und eustatischen Auswirkungen gesetzt. Der zeitliche Ablauf der Eisausdehnung und des Eisrùckzugs wàhrend der Fraser-Vereisung war deutlich asymmetrisch : die Vereisung begann um etwa 29 000 Jahre v.u.Z., erreichte ihren Hôchststand zwischen 14 500 und 14 000 Jahren v.u.Z. und die Enteisung war weitgehend vollendet um 11 500 Jahre v.u.Z. Der grôfîte Tail dieses Zeitraums scheint von einer alpinen Vereisung beherrscht gewesen zu sein, welche eindrucksvolle Erosions-Landformen hervorbrachte. Eine Kordilleren-Eisdecke existierte nur von etwa 19 000 bis 13 500 Jahre v.u.Z. Eine altère Vereisung, môglicherweise aus dem frùhen Wisconsin konnte anhand ausgedehnter Anlagen von glazialen Ablagerungen, die sich unter nichtglazialen Sedimenten des mittleren Wiskonsin befinden, identifiziert werden. Abgelagerte Bildungen aus dem Spàttertiâr bis zum mittleren Pleistozân wurden in Verbindung mit vulkanischen Sequenzen in den Bergen der Sùdkùste und dem zentralen Landesinnern und mittels palàomagnetischen Studien im sûdlichen Landesinnern datiert

X Chromosome Evolution in Cetartiodactyla

The phenomenon of a remarkable conservation of the X chromosome in eutherian mammals has been first described by Susumu Ohno in 1964. A notable exception is the cetartiodactyl X chromosome, which varies widely in morphology and G-banding pattern between species. It is hypothesized that this sex chromosome has undergone multiple rearrangements that changed the centromere position and the order of syntenic segments over the last 80 million years of Cetartiodactyla speciation. To investigate its evolution we have selected 26 evolutionarily conserved bacterial artificial chromosome (BAC) clones from the cattle CHORI-240 library evenly distributed along the cattle X chromosome. High-resolution BAC maps of the X chromosome on a representative range of cetartiodactyl species from different branches: pig (Suidae), alpaca (Camelidae), gray whale (Cetacea), hippopotamus (Hippopotamidae), Java mouse-deer (Tragulidae), pronghorn (Antilocapridae), Siberian musk deer (Moschidae), and giraffe (Giraffidae) were obtained by fluorescent in situ hybridization. To trace the X chromosome evolution during fast radiation in specious families, we performed mapping in several cervids (moose, Siberian roe deer, fallow deer, and Pere David’s deer) and bovid (muskox, goat, sheep, sable antelope, and cattle) species. We have identified three major conserved synteny blocks and rearrangements in different cetartiodactyl lineages and found that the recently described phenomenon of the evolutionary new centromere emergence has taken place in the X chromosome evolution of Cetartiodactyla at least five times. We propose the structure of the putative ancestral cetartiodactyl X chromosome by reconstructing the order of syntenic segments and centromere position for key groups

A High Density SNP Array for the Domestic Horse and Extant Perissodactyla: Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies

An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ∼43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50–100 kb and reached background levels within 1–2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of ∼750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under grant agreement n8 223175 (HEALTH-F2–2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ABCFS and OFBCR work was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement t by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M.C.S. is a NHMRC Senior Research Fellow. The OFBCR work was also supported by the Canadian Institutes of Health Research ‘CIHR Team in Familial Risks of Breast Cancer’ program. The ABCS was funded by the Dutch Cancer Society Grant no. NKI2007-3839 and NKI2009-4363. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Programme of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E.S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). I.T. is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental l and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital.The CNIO-BCS was supported by the Genome Spain Foundation the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. D.A. was supported by a Fellowship from the Michael Manzella Foundation (MMF) and was a participant in the CNIO Summer Training Program. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence e data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine , Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by a research grant from Takeda Science Foundation , by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (to N.B), and the Friends of Hannover Medical School (to N.B.). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Stockholm Cancer Foundation and the Swedish Cancer Society. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation , the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC (199600). G.C.T. and P.W. are supported by the NHMRC. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Federal Ministry of Education Research (BMBF) Germany (01KH0402), the Hamburg Cancer Society and the German Cancer Research Center (DKFZ). MBCSG is supported by grants from the Italian Association ciation for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’). The MCBCS was supported by the NIH grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (grant CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant PSR-SIIRI-701). MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19,tel:08/1/35/19./550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to A.L.B.D., FUGE-NFR 181600/ V11 to V.N.K. and a Swizz Bridge Award to A.L.B.D.). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NLCP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. pKARMA is a combination of the KARMA and LIBRO-1 studies. KARMA was supported by Ma¨rit and Hans Rausings Initiative Against Breast Cancer. KARMA and LIBRO-1 were supported the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linnaeus Centre (Contract ID 70867902) financed by the Swedish Research Council. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The SBCS was supported by Yorkshire Cancer Research S305PA, S299 and S295. Funding for the SCCS was provided by NIH grant R01 CA092447. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the National Medical Research Council Start-up Grant and Centre Grant (NMRC/CG/NCIS /2010). The recruitment of controls by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC) was funded by the Biomedical Research Council (grant number: 05/1/21/19/425). SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. K. J. is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. The TNBCC was supported by the NIH grant (CA128978), the Breast Cancer Research Foundation , Komen Foundation for the Cure, the Ohio State University Comprehensive Cancer Center, the Stefanie Spielman Fund for Breast Cancer Research and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. Part of the TNBCC (DEMOKRITOS) has been co-financed by the European Union (European Social Fund – ESF) and Greek National Funds through the Operational Program ‘Education and Life-long Learning’ of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. The TWBCS is supported by the Institute of Biomedical Sciences, Academia Sinica and the National Science Council, Taiwan. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.This is the advanced access published version distributed under a Creative Commons Attribution License 2.0, which can also be viewed on the publisher's webstie at: http://hmg.oxfordjournals.org/content/early/2014/07/04/hmg.ddu311.full.pdf+htm

Is autoimmunity the Achilles' heel of cancer immunotherapy?

The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it