Browsing by Subject "FAMILIES"

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  • Seppala, Toni T.; Ahadova, Aysel; Dominguez-Valentin, Mev; Macrae, Finlay; Evans, D. Gareth; Therkildsen, Christina; Sampson, Julian; Scott, Rodney; Burn, John; Möslein, Gabriela; Bernstein, Inge; Holinski-Feder, Elke; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Lautrup, Charlotte Kvist; Lindblom, Annika; Plazzer, John-Paul; Winship, Ingrid; Tjandra, Douglas; Katz, Lior H.; Aretz, Stefan; Hueneburg, Robert; Holzapfel, Stefanie; Heinimann, Karl; Della Valle, Adriana; Neffa, Florencia; Gluck, Nathan; Cappel, Wouter H. de Vos Tot Nederveen; Vasen, Hans; Morak, Monika; Steinke-Lange, Verena; Engel, Christoph; Rahner, Nils; Schmiegel, Wolff; Vangala, Deepak; Thomas, Huw; Green, Kate; Lalloo, Fiona; Crosbie, Emma J.; Hill, James; Capella, Gabriel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; ten Broeke, Sanne; Nielsen, Maartje; Ljungmann, Ken; Nakken, Sigve; Lindor, Noralane; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka-Pekka; Kalager, Mette; Moller, Pal (2019)
    BackgroundRecent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.MethodsTo inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.ResultsStage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within 3.5years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p=0.34). The cancers detected more than 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.
  • Low, Yen Ling; Li, Yuqing; Humphreys, Keith; Thalamuthu, Anbupalam; Li, Yi; Darabi, Hatef; Wedren, Sara; Bonnard, Carine; Czene, Kamila; Iles, Mark M.; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Nevanlinna, Heli; Hall, Per; Liu, Edison T.; Liu, Jianjun (2010)
  • Mattila, Henna; Schindler, Martin; Isotalo, Jarkko; Ikonen, Tarja; Vihinen, Mauno; Oja, Hannu; Tammela, Teuvo L. J.; Wahlfors, Tiina; Schleutker, Johanna (2011)
  • Hoggart, Clive J.; Venturini, Giulia; Mangino, Massimo; Gomez, Felicia; Ascari, Giulia; Zhao, Jing Hua; Teumer, Alexander; Winkler, Thomas W.; Tsernikova, Natalia; Luan, Jian'an; Mihailov, Evelin; Ehret, Georg B.; Zhang, Weihua; Lamparter, David; Esko, Tonu; Mace, Aurelien; Rueeger, Sina; Bochud, Pierre-Yves; Barcella, Matteo; Dauvilliers, Yves; Benyamin, Beben; Evans, David M.; Hayward, Caroline; Lopez, Mary F.; Franke, Lude; Russo, Alessia; Heid, Iris M.; Salvi, Erika; Vendantam, Sailaja; Arking, Dan E.; Boerwinkle, Eric; Chambers, John C.; Fiorito, Giovanni; Grallert, Harald; Guarrera, Simonetta; Homuth, Georg; Huffman, Jennifer E.; Porteous, David; Moradpour, Darius; Iranzo, Alex; Hebebrand, Johannes; Kemp, John P.; Lammers, Gert J.; Aubert, Vincent; Heim, Markus H.; Martin, Nicholas G.; Montgomery, Grant W.; Peraita-Adrados, Rosa; Santamaria, Joan; Generation Scotland Consortium; LifeLines Cohort Study; GIANT Consortium; Lokki, Marja-Liisa (2014)
  • Jiao, Xiang; Aravidis, Christos; Marikkannu, Rajeshwari; Rantala, Johanna; Picelli, Simone; Adamovic, Tatjana; Liu, Tao; Maguire, Paula; Kremeyer, Barbara; Luo, Liping; Von Holst, Susanna; Kontham, Vinaykumar; Thutkawkorapin, Jessada; Margolin, Sara; Du, Quan; Lundin, Johanna; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Ambrosone, Christine B.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Beckmann, Matthias W.; Blomqvist, Carl; Blot, William; Boeckx, Bram; Bojesen, Stig E.; Bonanni, Bernardo; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Bruning, Thomas; Burwinkel, Barbara; Cai, Qiuyin; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Deming-Halverson, Sandra L.; Devilee, Peter; dos-Santos-Silva, Isabel; Dork, Thilo; Eriksson, Mikael; Fasching, Peter A.; Nevanlinna, Heli; NBCS Collaborators; kConFab AOCS Investigators (2017)
    Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
  • Palmio, Johanna; Sandell, Satu; Hanna, Michael G.; Mannikko, Roope; Penttila, Sini; Udd, Bjarne (2017)
    Objective: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation. Methods: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp. Results: The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise-and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation. Conclusions: The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder SCN4A mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.
  • Gertz, Edward Michael; Hiekkalinna, Tero; Le Digabel, Sebastien; Audet, Charles; Terwilliger, Joseph D.; Schaeffer, Alejandro A. (2014)
  • Makitie, Riikka E.; Kampe, Anders J.; Taylan, Fulya; Makitie, Outi (2017)
    Purpose of Review This review summarizes our current knowledge on primary osteoporosis in children with focus on recent genetic findings. Recent Findings Advances in genetic research, particularly next-generation sequencing, have found several genetic loci that associate with monogenic forms of inherited osteoporosis, widening the scope of primary osteoporosis beyond classical osteogenesis imperfecta. New forms of primary osteoporosis, such as those related to WNT1, PLS3, and XYLT2, have identified defects outside the extracellular matrix components and collagen-related pathways, in intracellular cascades directly affecting bone cell function. Summary Primary osteoporosis can lead to severe skeletal morbidity, including abnormal longitudinal growth, compromised bone mass gain, and noticeable fracture tendency beginning at childhood. Early diagnosis and timely care are warranted to ensure the best achievable bone health. Future research will most likely broaden the spectrum of primary osteoporosis, hopefully provide more insight into the genetics governing bone health, and offer new targets for treatment.
  • Korhonen, Tellervo; Loukola, Anu; Wedenoja, Juho; Nyman, Emma; Latvala, Antti; Broms, Ulla; Happola, Anja; Paunio, Tiina; Schrage, Andrew J.; Vink, Jaqueline M.; Mbarek, Hamdi; Boomsma, Dorret I.; Penninx, Brenda W. J. H.; Pergadia, Michele L.; Madden, Pamela A. F.; Kaprio, Jaakko (2014)
  • Pelttari, Liisa M.; Nurminen, Riikka; Gylfe, Alexandra; Aaltonen, Lauri A.; Schleutker, Johanna; Nevanlinna, Heli (2012)
  • GEMO Study Collaborators; EMBRACE Collaborators; OCGN Investigators; HEBON Investigators; kConFab Investigators; Lakeman, Inge M. M.; van den Broek, Alexandra J.; Vos, Julien A. M.; Nevanlinna, Heli (2021)
    Purpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
  • Mars, Nina; Widen, Elisabeth; Meretoja, Tuomo; Kerminen, Sini; Pirinen, Matti; Della Briotta Parolo, Pietro; Palta, Priit; FinnGen; Palotie, Aarno; Kaprio, Jaakko; Joensuu, Heikki; Daly, Mark; Ripatti, Samuli; Pärn, Kalle; Tienari, Pentti (2020)
    Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90(th) percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS (>90(th) percentile), and decreases to 49% (30-68%) with a low PRS (
  • Seppala, Toni T.; Pylvanainen, Kirsi; Mecklin, Jukka-Pekka (2017)
    Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged 418 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06-1.10), family gene (OR 2.83; 1.75-4.57 for MLH1 and 2.59; 1.47-4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82-9.03), no siblings (OR 4.63; 2.64-8.10), and parent under endoscopic surveillance (OR 5.22; 2.41-11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance.
  • Naukkarinen, Jussi; Surakka, Ida; Pietiläinen, Kirsi H.; Rissanen, Aila; Salomaa, Veikko; Ripatti, Samuli; Yki-Järvinen, Hannele; van Duijn, Cornelia M.; Wichmann, H. -Erich; Kaprio, Jaakko; Taskinen, Marja-Riitta; Peltonen, Leena; ENGAGE Consortium (2010)
  • Ganna, Andrea; Ortega-Alonso, Alfredo; Havulinna, Aki; Salomaa, Veikko; Kaprio, Jaakko; Pedersen, Nancy L.; Sullivan, Patrick F.; Ingelsson, Erik; Hultman, Christina M.; Magnusson, Patrik K. E. (2013)
  • Vornanen, Marleena Emilia; Aktan-Collan, Katja Irmeli; Hallowell, Nina; Konttinen, Hanna Marja; Kääriäinen, Helena; Haukkala, Ari Heikki (2018)
    Lowered costs of genomic sequencing facilitate analyzing large segments of genetic data. Ethical debate has focused on whether and what kind of incidental or secondary findings (SFs) to report, and how to obtain valid informed consent. However, people’s support needs after receiving SFs have received less attention. We explored Finnish adults’ perspectives on reporting genetic SFs. In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. Major themes were immediate shock, dealing with worry and heightened risk, fear of being left alone to deal with SFs, disclosing to family, and identified support needs. Despite their willingness to receive SFs, participants were concerned about being left alone to deal with them. Empathetic expert support and timely access to preventive care were seen as essential to coping with shock and worry, and disclosing SFs to family. Discussion around SFs needs to concern not only which findings to report, but also how healthcare systems need to prepare for providing timely access to preventive care and support for individuals and families.