Browsing by Subject "OVARIAN-CANCER"

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  • Gaber, Alexander; Nodin, Bjorn; Hotakainen, Kristiina; Nilsson, Elise; Stenman, Ulf-Håkan; Bjartell, Anders; Birgisson, Helgi; Jirstrom, Karin (2010)
  • Rebbeck, Timothy R.; Friebel, Tara M.; Mitra, Nandita; Wan, Fei; Chen, Stephanie; Andrulis, Irene L.; Apostolou, Paraskevi; Arnold, Norbert; Arun, Banu K.; Barrowdale, Daniel; Benitez, Javier; Berger, Raanan; Berthet, Pascaline; Borg, Ake; Buys, Saundra S.; Caldes, Trinidad; Carter, Jonathan; Chiquette, Jocelyne; Claes, Kathleen B. M.; Couch, Fergus J.; Cybulski, Cezary; Daly, Mary B.; de la Hoya, Miguel; Diez, Orland; Domchek, Susan M.; Nathanson, Katherine L.; Durda, Katarzyna; Ellis, Steve; Evans, D. Gareth; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Glendon, Gord; Godwin, Andrew K.; Greene, Mark H.; Gronwald, Jacek; Hahnen, Eric; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V. O.; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; John, Esther M.; Karlan, Beth Y.; Nevanlinna, Heli; EMBRACE; HEBON; KConFab Investigators (2016)
    Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p <0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p <0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
  • Kauko, Otto; Laajala, Teemu Daniel; Jumppanen, Mikael; Hintsanen, Petteri; Suni, Veronika; Haapaniemi, Pekka; Corthals, Garry; Aittokallio, Tero; Westermarck, Jukka; Imanishi, Susumu Y. (2015)
    Hyperactivated RAS drives progression of many human malignancies. However, oncogenic activity of RAS is dependent on simultaneous inactivation of protein phosphatase 2A (PP2A) activity. Although PP2A is known to regulate some of the RAS effector pathways, it has not been systematically assessed how these proteins functionally interact. Here we have analyzed phosphoproteomes regulated by either RAS or PP2A, by phosphopeptide enrichment followed by mass-spectrometry-based label-free quantification. To allow data normalization in situations where depletion of RAS or PP2A inhibitor CIP2A causes a large uni-directional change in the phosphopeptide abundance, we developed a novel normalization strategy, named pairwise normalization. This normalization is based on adjusting phosphopeptide abundances measured before and after the enrichment. The superior performance of the pairwise normalization was verified by various independent methods. Additionally, we demonstrate how the selected normalization method influences the downstream analyses and interpretation of pathway activities. Consequently, bioinformatics analysis of RAS and CIP2A regulated phosphoproteomes revealed a significant overlap in their functional pathways. This is most likely biologically meaningful as we observed a synergistic survival effect between CIP2A and RAS expression as well as KRAS activating mutations in TCGA pan-cancer data set, and synergistic relationship between CIP2A and KRAS depletion in colony growth assays.
  • Gavrilyuk, Oxana; Braaten, Tonje; Weiderpass, Elisabete; Licaj, Idlir; Lund, Eiliv (2018)
    IntroductionLifetime number of years of menstruation (LNYM) reflects a woman's cumulative exposure to endogenous estrogen and can be used as a measure of the combined effect of reproductive factors related to endometrial cancer (EC) risk. Material and methodsWe aimed to study the association between LNYM and EC risk among postmenopausal women and calculate the population attributable fraction of EC for different LNYM categories. Our study sample consisted of 117589 women from the Norwegian Women and Cancer (NOWAC) Study. All women were aged 30-70years at enrollment and completed a baseline questionnaire between 1991 and 2006. Women were followed up for EC to December 2014 through linkages to national registries. We used Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals (95% CIs), adjusted for potential confounders. ResultsIn all, 720 women developed EC. We found a statistically significant, positive dose-response relationship between LNYM and EC, with a 9.1% higher risk for each additional year of LNYM (P for trend ConclusionsOur study supports that increasing LNYM is an important and independent predictor of EC risk.
  • Normann, Lisa Svartdal; Aure, Miriam Ragle; Leivonen, Suvi-Katri; Haugen, Mads Haugland; Hongisto, Vesa; Kristensen, Vessela N.; Maelandsmo, Gunhild Mari; Sahlberg, Kristine Kleivi (2021)
    HER2-positive (HER2+) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2+breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2+cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2+breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2+breast cancer (OS: p=0.039; BCSS: p=0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2+breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2+breast cancers.
  • Liikanen, Ilkka; Ahtiainen, Laura; Hirvinen, Mari L. M.; Bramante, Simona; Cerullo, Vincenzo; Nokisalmi, Petri; Hemminki, Otto; Diaconu, Iulia; Pesonen, Sari; Koski, Anniina; Kangasniemi, Lotta; Pesonen, Saila K.; Oksanen, Minna; Laasonen, Leena; Partanen, Kaarina; Joensuu, Timo; Zhao, Fang; Kanerva, Anna; Hemminki, Akseli (2013)
  • Hemminki, Otto; dos Santos, Joao Manuel; Hemminki, Akseli (2020)
    In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains. As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors. Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
  • Southey, Melissa C.; Goldgar, David E.; Winqvist, Robert; Pylkas, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D.; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J.; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L.; Doerk, Thilo; Claes, Kathleen B. M.; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A.; Dowty, James G.; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K.; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Pelttari, Liisa M.; Butzow, Ralf; kConFab Investigators; Australian Ovarian Canc Study Grp (2016)
    Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
  • Sköld, Amilla; Bjorge, Tone; Ekbom, Anders; Engeland, Anders; Gissler, Mika; Grotmol, Tom; Madanat-Harjuoja, Laura; Ording, Anne Gulbech; Trabert, Britton; Tretli, Steinar; Troisi, Rebecca; Sorensen, Henrik Toft; Glimelius, Ingrid (2020)
    Background Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. Methods Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970-2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases' birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. Results The risk of SCSTs, but not GCTs, decreased with higher age at last birth [>= 40 versus
  • Pelttari, Liisa M.; Kiiski, Johanna I.; Ranta, Salla; Vilske, Sara; Blomqvist, Carl; Aittomaki, Kristiina; Nevanlinna, Heli (2015)
    Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51 and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls. Our results suggest that RAD51, XRCC3, and XRCC2 do not substantially contribute to breast cancer predisposition in the Finnish population.
  • Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Doerk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Dunning, Alison M.; Garcia-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; Nordestgaard, Borge G.; Benitez, Javier; Gonzalez-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Bruening, Thomas; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli; kConFab AOCS Investigators (2016)
    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10(-16)) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10(-11)), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
  • Brunham, Robert C.; Paavonen, Jorma (2020)
    Lower genital tract infection and bloodborne spread of infection are the two principal modes for infection of the upper genital tract or for infection of the fetus, neonate or infant. Treponema pallidum and human immunodeficiency virus (HIV) are the two most common bloodborne pathogens that infect the fetus, neonate or infant. Most infections of the upper genital tract, however, spread along epithelial surfaces from the vagina or cervix to the upper genital tract or chorioamnion, fetus, neonate or infant. These infections are caused by either pathogens associated with a dysbiotic vaginal microbiome or those that are sexually transmitted. The clinical syndromes that these pathogens produce in the lower genital tract were discussed in part one of this review. We now discuss the syndromes and pathogens that affect the upper genital tract of both non-pregnant and pregnant women as well as fetus, neonate and infant.
  • Pelttari, Liisa M.; Nurminen, Riikka; Gylfe, Alexandra; Aaltonen, Lauri A.; Schleutker, Johanna; Nevanlinna, Heli (2012)
  • Jaiswal, Alok; Peddinti, Gopal; Akimov, Yevhen; Wennerberg, Krister; Kuznetsov, Sergey; Tang, Jing; Aittokallio, Tero (2017)
    Background: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity. Methods: We performed a systematic, quantitative analysis of the consistency between two genome-wide shRNA screens conducted on a compendium of cancer cell lines, and also compared several gene summarization methods for inferring gene essentiality from shRNA level data. We then devised novel concepts of seed essentiality and shRNA family, based on seed region sequences of shRNAs, to study in-depth the contribution of seed-mediated off-target effects to the consistency of the two screens. We further investigated two seed-sequence properties, seed pairing stability, and target abundance in terms of their capability to minimize the off-target effects in post-screening data analysis. Finally, we applied this novel methodology to identify genetic interactions and synthetic lethal partners of cancer drivers, and confirmed differential essentiality phenotypes by detailed CRISPR/Cas9 experiments. Results: Using the novel concepts of seed essentiality and shRNA family, we demonstrate how genome-wide loss-of-function profiling of a common set of cancer cell lines can be actually made fairly reproducible when considering seed-mediated off-target effects. Importantly, by excluding shRNAs having higher propensity for off-target effects, based on their seed-sequence properties, one can remove noise from the genome-wide shRNA datasets. As a translational application case, we demonstrate enhanced reproducibility of genetic interaction partners of common cancer drivers, as well as identify novel synthetic lethal partners of a major oncogenic driver, PIK3CA, supported by a complementary CRISPR/Cas9 experiment. Conclusions: We provide practical guidelines for improved design and analysis of genome-wide loss-of-function profiling and demonstrate how this novel strategy can be applied towards improved mapping of genetic dependencies of cancer cells to aid development of targeted anticancer treatments.
  • Ranki, Tuuli; Hemminki, Akseli (2010)
  • Pulkka, Olli-Pekka; Nilsson, Bengt; Sarlomo-Rikala, Maarit; Reichardt, Peter; Eriksson, Mikael; Hall, Kirsten Sundby; Wardelmann, Eva; Vehtari, Aki; Joensuu, Heikki; Sihto, Harri (2017)
    Background: The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown. Methods: Influence of SLUG expression on cell proliferation and viability were investigated in GIST48 and GIST882 cell lines. The association between tumour SLUG expression in immunohistochemistry and recurrence-free survival (RFS) was studied in two clinical GIST series, one with 187 patients treated with surgery alone, and another one with 313 patients treated with surgery and adjuvant imatinib. Results: SLUG downregulation inhibited cell proliferation, induced cell death in both cell lines, and sensitised GIST882 cells to lower imatinib concentrations. SLUG was expressed in 125 (25.0%) of the 500 clinical GISTs evaluated, and expression was associated with several factors linked with unfavourable prognosis. SLUG expression was associated with unfavourable RFS both when patients were treated with surgery alone (HR = 3.40, 95% CI = 1.67-6.89, P = 0.001) and when treated with surgery plus adjuvant imatinib (HR = 1.83, 95% CI = 1.29-2.60, P = 0.001). Conclusions: GIST patients with high tumour SLUG expression have unfavourable RFS. SLUG may mediate pro-survival signalling in GISTs.
  • Saraswat, Mayank; Mäkitie, Antti; Tohmola, Tiialotta; Dickinson, Amy; Saraswat, Shruti; Joenväärä, Sakari; Renkonen, Suvi (2018)
    Purpose Experimental design There are no blood biomarkers to detect early-stage oral cavity squamous cell carcinoma (OSCC) prior to clinical signs. Most OSCC incidence is associated with significant morbidity and poor survival. The authors aimed to use mass-spectrometry (MS) technology to find specific N-glycopeptides potentially serving as serum biomarkers for preclinical OSCC screening. Serum samples from 14 patients treated for OSCC (stage I or stage IV) with 12 age- and sex-matched controls are collected. Quantitative label-free N-glycoproteomics is performed, with MS/MS analysis of the statistically significantly different N-glycopeptides. Results Conclusions and clinical relevance Combined with a database search using web-based software (GlycopeptideID), MS/MS provided detailed N-glycopeptide information, including glycosylation site, glycan composition, and proposed structures. Thirty-eight tryptic N-glycopeptides are identified, having 19 unique N-glycosylation sites representing 14 glycoproteins. OSCC patients, including stage I tumors, can be differentiated from healthy controls based on the expression levels of these glycoforms. N-glycopeptides of IgG1, IgG4, haptoglobin, and transferrin have statistically significant different abundances between cases and controls. The authors are the first to suggest specific N-glycopeptides to serve as potential serum biomarkers to detect preclinical OSCC in patients. These N-glycopeptides are the lead candidates for validation as future diagnostic modalities of OSCC as early as stage I.
  • Shimelis, Hermela; LaDuca, Holly; Hu, Chunling; Hart, Steven N.; Na, Jie; Thomas, Abigail; Akinhanmi, Margaret; Moore, Raymond M.; Brauch, Hiltrud; Cox, Angela; Eccles, Diana M.; Ewart-Toland, Amanda; Fasching, Peter A.; Fostira, Florentia; Garber, Judy; Godwin, Andrew K.; Konstantopoulou, Irene; Nevanlinna, Heli; Sharma, Priyanka; Yannoukakos, Drakoulis; Yao, Song; Feng, Bing-Jian; Davis, Brigette Tippin; Lilyquist, Jenna; Pesaran, Tina; Goldgar, David E.; Polley, Eric C.; Dolinsky, Jill S.; Couch, Fergus J. (2018)
    Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.
  • Magnussen, Synnove; Hadler-Olsen, Elin; Latysheva, Nadezhda; Pirila, Emma; Steigen, Sonja E.; Hanes, Robert; Salo, Tuula; Winberg, Jan-Olof; Uhlin-Hansen, Lars; Svineng, Gunbjorg (2014)