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31 results on '"Vuorela M"'

1. Assembly of the β4-integrin interactome based on proximal biotinylation in the presence and absence of heterodimerization

Author

Myllymäki, S.-M. (Satu-Marja), Kämäräinen, U.-R. (Ulla-Reetta), Liu, X. (Xiaonan), Pereira Cruz, S. (Sara), Miettinen, S. (Sini), Vuorela, M. (Mikko), Varjosalo, M. (Markku), Manninen, A. (Aki), Myllymäki, S.-M. (Satu-Marja), Kämäräinen, U.-R. (Ulla-Reetta), Liu, X. (Xiaonan), Pereira Cruz, S. (Sara), Miettinen, S. (Sini), Vuorela, M. (Mikko), Varjosalo, M. (Markku), and Manninen, A. (Aki)

Abstract

Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have used proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia-specific β4-integrin that, as α6β4-heterodimer, forms the core of HDs. The analysis identified ∼150 proteins that were specifically labeled by BirA-tagged integrin-β4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-β4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate β4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, although establishment of functional HDs depends on the formation of α6β4-heterodimers, the assembly of β4-interactome was not strictly dependent on α6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the β4-integrin.

Published
2019

2. RAD51B in familial breast cancer.

Author

Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., Anderson L., Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., and Anderson L.

Abstract

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.

Published
2017

3. RAD51B in familial breast cancer

Author

Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Dörk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, García-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, Dos-Santos-silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guénel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, González-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Brüning, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, and Dumont, M

Abstract

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 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 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.

Published
2016

4. RAD51B in Familial Breast Cancer

Author

Brusgaard, K, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Doerk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, Garcia-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guenel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, Gonzalez-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Bruening, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Dumont, M, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Grip, M, Andrulis, IL, Glendon, G, Devilee, P, Seynaeve, C, Hooning, MJ, Collee, M, Cox, A, Cross, SS, Shah, M, Luben, RN, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Couch, FJ, Yannoukakos, D, Orr, N, Swerdlow, A, Darabi, H, Li, J, Czene, K, Hall, P, Easton, DF, Mattson, J, Blomqvist, C, Aittomaki, K, Nevanlinna, H, Brusgaard, K, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Doerk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, Garcia-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guenel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, Gonzalez-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Bruening, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Dumont, M, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Grip, M, Andrulis, IL, Glendon, G, Devilee, P, Seynaeve, C, Hooning, MJ, Collee, M, Cox, A, Cross, SS, Shah, M, Luben, RN, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Couch, FJ, Yannoukakos, D, Orr, N, Swerdlow, A, Darabi, H, Li, J, Czene, K, Hall, P, Easton, DF, Mattson, J, Blomqvist, C, Aittomaki, K, and Nevanlinna, H

Abstract

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.

Published
2016

5. Role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes and rare copy number variants in hereditary predisposition to breast cancer

Author

Vuorela, M. (Mikko), Winqvist, R. (Robert), and Pylkäs, K. (Katri)

Subjects
DNA copy number variations, DNA-kopiomäärän vaihtelut, estrogeenit, perinnöllisyystiede, tumor suppressor protein p53, ubiquitin-conjugating enzymes, DNA-mutaatioanalyysi, rinnan kasvaimet, n sitojaproteiinit [DNA], ituradan mutaatio, Fanconi anemia, DNA-binding proteins, DNA mutational analysis, breast neoplasms, genetics, ubikitiini-konjugaatioentsyymit, germ-line mutation, Fanconin anemia, kasvainsalpaajaproteiini p53, estrogens
Abstract

Mutations in the currently known breast cancer susceptibility genes account for only 25–30% of all familial cases. Novel susceptibility genes can be identified by several methods, including candidate gene re-sequencing and genome-wide microarrays. We have applied microarrays for the detection of a new genomic variation class, copy number variants (CNVs), which potentially could disrupt genes in multiple pathways related to breast cancer susceptibility. The aim of the current study was to evaluate the role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes in breast cancer susceptibility as well as to study if rare CNVs are associated with the predisposition to this disease. The analysis of 123 familial breast cancer cases revealed altogether nine different changes in the RNF8 and UBC13 candidate genes. However, none of the observed alterations were considered pathogenic. No alterations were observed in MMS2. The obtained results suggest that breast cancer predisposing alterations in RNF8, UBC13 and MMS2 are rare, or even absent. The RAD51C mutation screening of 147 familial breast cancer cases and 232 unselected ovarian cancer cases revealed two deleterious mutations: c.-13_14del27 was observed in a breast cancer case with familial history of ovarian cancer and c.774delT in an ovarian cancer case. Both mutations were absent in the control cohort. The results of the study support the hypothesis that rare variants of RAD51C predispose predominantly to ovarian cancer. A genome-wide scan of CNVs was performed for 103 familial breast cancer cases and 128 controls. The biological networks of the genes disrupted by CNVs were different between the two groups. In familial breast cancer cases, the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity (P=0.0211). Biological network analysis showed that the disrupted genes were closely related to estrogen signaling and TP53-centered tumor suppressor network, and this result was confirmed by the analysis of an independent young breast cancer cohort of 75 cases. These results suggest that rare CNVs represent an alternative source of genetic variation contributing to hereditary risk for breast cancer. Tiivistelmä Tunnetut rintasyöpäalttiusgeenien mutaatiot selittävät vain 25–30 prosenttia kaikista perinnöllisistä rintasyöpätapauksista. Uusia alttiusgeenejä voidaan tunnistaa useilla eri menetelmillä, kuten kandidaattigeenien mutaatiokartoituksella ja genomin-laajuisilla mikrosirutekniikoilla. Tässä tutkimuksessa sovelsimme mikrosirutekniikkaa uuden geneettisen variaatioluokan, kopiolukuvariaation (CNV), tutkimiseen. CNV:t voivat vaurioittaa lukuisia rintasyöpäalttiuteen liittyviä biokemiallisia reittejä. Tämän tutkimuksen tarkoitus oli arvioida RNF8-, UBC13-, MMS2- ja RAD51C -DNA- vauriovastegeenien sekä harvinaisten CNV:iden yhteyttä rintasyöpä-alttiuteen. 123 familiaalisen rintasyöpätapauksen analyysissä löytyi yhteensä yhdeksän muutosta RNF8- ja UBC13-geeneistä, joista yksikään ei osoittautunut patogeeniseksi. MMS2-geenissä ei havaittu muutoksia. Tulosten perusteella rintasyövälle altistavat muutokset RNF8-, UBC13- ja MMS2- geeneissä ovat joko erittäin harvinaisia tai niitä ei esiinny lainkaan. RAD51C-geenin mutaatiokartoitus 147 familiaalisesta rintasyöpätapauksesta sekä 232 valikoimattomasta munasarjasyöpätapauksesta paljasti kaksi haitallista mutaatiota. c.-13_14del27 havaittiin rintasyöpäpotilaalla, jonka suvussa esiintyi munasarjasyöpää, ja c.774delT todettiin munasarjasyöpäpotilaalta. Kumpaakaan mutaatiota ei havaittu verrokkiaineistossa. Tulokset vahvistavat hypoteesia RAD51C-geenin harvinaisten varianttien yhteydestä pääasiassa munasarjasyöpäriskiin. CNV:iden genomin-laajuinen skannaaminen suoritettiin 103 familiaaliselle rintasyöpätapaukselle ja 128 verrokille. CNV:iden häiritsemien geenien muodostamat biologiset verkostot olivat erilaiset näiden kahden ryhmän välillä. Familiaalisilla rintasyöpätapauksilla havaitut CNV:t vaikuttivat geeneihin, jotka olivat voimakkaasti korostuneita genomin eheyttä ylläpitävissä tehtävissä (P=0.0211). Biologisten verkostojen analyysi paljasti, että CNV:iden vahingoittamat geenit liittyivät läheisesti estrogeenisignalointiin sekä TP53-tuumorisupressoriverkostoon, ja tämä tulos vahvistettiin analysoimalla riippumatonta nuorista rintasyöpäpotilaista koostuvaa kohorttia (N=75). Tutkimuksen tulosten mukaan harvinaiset CNV:t ovat vaihtoehtoinen geneettisen variaation lähde perinnölliseen rintasyöpäalttiuteen.

Published
2013

8. Role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes and rare copy number variants in hereditary predisposition to breast cancer

Author

Winqvist, R. (Robert), Pylkäs, K. (Katri), Vuorela, M. (Mikko), Winqvist, R. (Robert), Pylkäs, K. (Katri), and Vuorela, M. (Mikko)

Abstract

Mutations in the currently known breast cancer susceptibility genes account for only 25–30% of all familial cases. Novel susceptibility genes can be identified by several methods, including candidate gene re-sequencing and genome-wide microarrays. We have applied microarrays for the detection of a new genomic variation class, copy number variants (CNVs), which potentially could disrupt genes in multiple pathways related to breast cancer susceptibility. The aim of the current study was to evaluate the role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes in breast cancer susceptibility as well as to study if rare CNVs are associated with the predisposition to this disease. The analysis of 123 familial breast cancer cases revealed altogether nine different changes in the RNF8 and UBC13 candidate genes. However, none of the observed alterations were considered pathogenic. No alterations were observed in MMS2. The obtained results suggest that breast cancer predisposing alterations in RNF8, UBC13 and MMS2 are rare, or even absent. The RAD51C mutation screening of 147 familial breast cancer cases and 232 unselected ovarian cancer cases revealed two deleterious mutations: c.-13_14del27 was observed in a breast cancer case with familial history of ovarian cancer and c.774delT in an ovarian cancer case. Both mutations were absent in the control cohort. The results of the study support the hypothesis that rare variants of RAD51C predispose predominantly to ovarian cancer. A genome-wide scan of CNVs was performed for 103 familial breast cancer cases and 128 controls. The biological networks of the genes disrupted by CNVs were different between the two groups. In familial breast cancer cases, the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity (P=0.0211). Biological network analysis showed that the disrupted genes were closely related to estrogen signaling and T, Tiivistelmä Tunnetut rintasyöpäalttiusgeenien mutaatiot selittävät vain 25–30 prosenttia kaikista perinnöllisistä rintasyöpätapauksista. Uusia alttiusgeenejä voidaan tunnistaa useilla eri menetelmillä, kuten kandidaattigeenien mutaatiokartoituksella ja genomin-laajuisilla mikrosirutekniikoilla. Tässä tutkimuksessa sovelsimme mikrosirutekniikkaa uuden geneettisen variaatioluokan, kopiolukuvariaation (CNV), tutkimiseen. CNV:t voivat vaurioittaa lukuisia rintasyöpäalttiuteen liittyviä biokemiallisia reittejä. Tämän tutkimuksen tarkoitus oli arvioida RNF8-, UBC13-, MMS2- ja RAD51C -DNA- vauriovastegeenien sekä harvinaisten CNV:iden yhteyttä rintasyöpä-alttiuteen. 123 familiaalisen rintasyöpätapauksen analyysissä löytyi yhteensä yhdeksän muutosta RNF8- ja UBC13-geeneistä, joista yksikään ei osoittautunut patogeeniseksi. MMS2-geenissä ei havaittu muutoksia. Tulosten perusteella rintasyövälle altistavat muutokset RNF8-, UBC13- ja MMS2- geeneissä ovat joko erittäin harvinaisia tai niitä ei esiinny lainkaan. RAD51C-geenin mutaatiokartoitus 147 familiaalisesta rintasyöpätapauksesta sekä 232 valikoimattomasta munasarjasyöpätapauksesta paljasti kaksi haitallista mutaatiota. c.-13_14del27 havaittiin rintasyöpäpotilaalla, jonka suvussa esiintyi munasarjasyöpää, ja c.774delT todettiin munasarjasyöpäpotilaalta. Kumpaakaan mutaatiota ei havaittu verrokkiaineistossa. Tulokset vahvistavat hypoteesia RAD51C-geenin harvinaisten varianttien yhteydestä pääasiassa munasarjasyöpäriskiin. CNV:iden genomin-laajuinen skannaaminen suoritettiin 103 familiaaliselle rintasyöpätapaukselle ja 128 verrokille. CNV:iden häiritsemien geenien muodostamat biologiset verkostot olivat erilaiset näiden kahden ryhmän välillä. Familiaalisilla rintasyöpätapauksilla havaitut CNV:t vaikuttivat geeneihin, jotka olivat voimakkaasti korostuneita genomin eheyttä ylläpitävissä tehtävissä (P=0.0211). Biologisten verkostojen analyysi paljasti, että CNV:iden vahingoittamat geenit liittyivät läheisesti estrogeenisignaloin

Published
2013

12. Horizontal freezing cools Helsinki metro drive.

Author

Vuorela M., Eronen T., Vuorela M., and Eronen T.

Abstract

Twin 6.5 m diameter metro tunnels were driven through saturated soil at a depth of 25 m in Helsinki with the aid of horizontal freezing. The soil around the perimeter of the tunnel bores was frozen by vapourising freon in the freeze tubes. A 2.5 m thick ice wall in sand and moraine developed during the freezing period of 55 days. The tunnel bores were excavated by cautious drilling and blasting. The advance was 1.2-1.8 m per round. Permanent tunnel linings were constructed by bolting together cast iron segments., Twin 6.5 m diameter metro tunnels were driven through saturated soil at a depth of 25 m in Helsinki with the aid of horizontal freezing. The soil around the perimeter of the tunnel bores was frozen by vapourising freon in the freeze tubes. A 2.5 m thick ice wall in sand and moraine developed during the freezing period of 55 days. The tunnel bores were excavated by cautious drilling and blasting. The advance was 1.2-1.8 m per round. Permanent tunnel linings were constructed by bolting together cast iron segments.

16. Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families

Author

Winqvist Robert, Pylkäs Katri, and Vuorela Mikko

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer. Methods The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing. Results Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility. Conclusions The present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.

Published
2011
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18. RAD51B in Familial Breast Cancer

Author

kConFab, Jonine Figueroa, Elinor J. Sawyer, Manjeet K. Bolla, Carl Blomqvist, Jaana M. Hartikainen, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Fredrick Schumacher, Vessela N. Kristensen, Graham G. Giles, Isabel dos-Santos-Silva, Kamila Czene, Douglas F. Easton, Qin Wang, Javier Benitez, Janet E. Olson, Georgia Chenevix-Trench, John L. Hopper, Alicia Beeghly-Fadiel, Hoda Anton-Culver, Paolo Radice, Aocs Investigators, Nick Orr, Jacques Simard, Mervi Grip, Salla Ranta, Fergus J. Couch, Marjanka K. Schmidt, Kristiina Aittomäki, Caroline Seynaeve, Ute Hamann, Johanna Schleutker, Hilde Janssen, Robert Luben, Anna González-Neira, Peter A. Fasching, Pascal Guénel, Anja Rudolph, Arto Mannermaa, Melissa C. Southey, Ian Tomlinson, Thérèse Truong, Alison M. Dunning, Margriet Collée, Robert Winqvist, Johanna Mattson, Mikko Vuorela, Sara Vilske, Anne Lise Børresen-Dale, Johanna I. Kiiski, Paolo Peterlongo, Anna Jakubowska, Paul D.P. Pharoah, Alfons Meindl, Anthony J. Swerdlow, Roger L. Milne, Hermann Brenner, Joe Dennis, Montserrat Garcia-Closas, Thomas Brüning, Christopher A. Haiman, Martine Dumont, Wei Zheng, Per Hall, Gord Glendon, Jingmei Li, Laurien Van Dyck, Susan L. Neuhausen, Simon S. Cross, Irene L. Andrulis, Peter Devilee, Annika Lindblom, Emily Hallberg, Diana Torres, Sofia Khan, Kyriaki Michailidou, Rita K. Schmutzler, Julian Peto, Harald Surowy, Børge G. Nordestgaard, Barbara Burwinkel, Natalia Bogdanova, Drakoulis Yannoukakos, Heli Nevanlinna, Jan Lubinski, Liisa M. Pelttari, Efraim H. Rosenberg, Hiltrud Brauch, Thilo Dörk, Angela Cox, Viivi Nevanlinna, Maartje J. Hooning, Volker Arndt, Anne Kallioniemi, Stig E. Bojesen, Jenny Chang-Claude, Hatef Darabi, Obstetrics & Gynecology, Clinical Genetics, Gastroenterology & Hepatology, Medical Oncology, Brusgaard, Klaus, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Thierry, B, Zeps, N, Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Heredity, XRCC2, Genotyping Techniques, lcsh:Medicine, Genome-wide association study, 14Q24.1 RAD51L1, VARIANTS, Geographical Locations, 3123 Gynaecology and paediatrics, Cancer screening, Breast Tumors, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, Ethnicities, lcsh:Science, Finland, Genetics, RISK, education.field_of_study, Multidisciplinary, GERMLINE MUTATIONS, Genomics, Middle Aged, 3. Good health, Ovarian Cancer, Europe, DNA-Binding Proteins, Genetic Mapping, Male breast cancer, Female, Cancer Screening, Research Article, medicine.medical_specialty, Heterozygote, General Science & Technology, Population, 3122 Cancers, Mutation, Missense, Single-nucleotide polymorphism, Variant Genotypes, Breast Neoplasms, Genome Complexity, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Breast Cancer, medicine, Cancer Detection and Diagnosis, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Evolutionary Biology, Population Biology, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Odds ratio, medicine.disease, ta3122, GENE, Introns, 030104 developmental biology, Haplotypes, FANCONI-ANEMIA, People and Places, lcsh:Q, Population Groupings, business, Ovarian cancer, Gynecological Tumors, Population Genetics, Finns
Abstract

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. ispartof: PLoS One vol:11 issue:5 ispartof: location:United States status: published

Published
2016

19. Tuberculosis in people with rheumatic disease in Finland 1995-2007: a nationwide retrospective register study.

Author

Vuorela M, Mars NJ, Salonen J, and Kauppi MJ

Abstract

Objectives: RA and its medication, especially TNF-α inhibitors, increase the risk of clinical tuberculosis (TB) infection. We aimed to investigate the clinical manifestations, incidence and temporal changes in TB occurring concurrently with rheumatic diseases (RDs) between 1995 and 2007., Methods: We combined the register of the Social Insurance Institution of Finland and the National Infectious Disease Register to find adult patients with reimbursed DMARDs and with a TB notification between 1995 and 2007. After reviewing the medical records, we described their clinical manifestations and medications, explored TB incidence trends using Poisson regression, and compared the incidence of TB with that of the general population., Results: We identified 291 patients with both TB and rheumatic disease (RD), 196 of whom had RA. Between 1995 and 2007, the incidence of TB in adult RD decreased from 58.8 to 30.0 per 100 000 (trend P < 0.001, average marginal effect -3.4/100 000 per year, 95% CI -4.4, -2.4). Compared with the general population, the incidence was ∼4-fold. Among RD patients, pulmonary TB was the most common form of TB (72.6%). Disseminated TB was present in 56 (19.6%) patients., Conclusion: The incidence of TB among RD patients was ∼4-fold that of the general population, and it declined between 1995 and 2007. Disseminated TB was present in nearly 20% of patients.

Published
2019
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20. Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization.

Author

Myllymäki SM, Kämäräinen UR, Liu X, Cruz SP, Miettinen S, Vuorela M, Varjosalo M, and Manninen A

Subjects
Animals, Biotinylation, Chromatography, Liquid, Dogs, Madin Darby Canine Kidney Cells, Protein Interaction Maps, Protein Multimerization, Tandem Mass Spectrometry, Integrin beta4 chemistry, Integrin beta4 metabolism, Proteomics methods
Abstract

Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have used proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia-specific β4-integrin that, as α6β4-heterodimer, forms the core of HDs. The analysis identified ∼150 proteins that were specifically labeled by BirA-tagged integrin-β4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-β4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate β4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, although establishment of functional HDs depends on the formation of α6β4-heterodimers, the assembly of β4-interactome was not strictly dependent on α6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the β4-integrin., (© 2019 Myllymäki et al.)

Published
2019
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21. RAD51B in Familial Breast Cancer.

Author

Pelttari LM, Khan S, Vuorela M, Kiiski JI, Vilske S, Nevanlinna V, Ranta S, Schleutker J, Winqvist R, Kallioniemi A, Dörk T, Bogdanova NV, Figueroa J, Pharoah PD, Schmidt MK, Dunning AM, García-Closas M, Bolla MK, Dennis J, Michailidou K, Wang Q, Hopper JL, Southey MC, Rosenberg EH, Fasching PA, Beckmann MW, Peto J, Dos-Santos-Silva I, Sawyer EJ, Tomlinson I, Burwinkel B, Surowy H, Guénel P, Truong T, Bojesen SE, Nordestgaard BG, Benitez J, González-Neira A, Neuhausen SL, Anton-Culver H, Brenner H, Arndt V, Meindl A, Schmutzler RK, Brauch H, Brüning T, Lindblom A, Margolin S, Mannermaa A, Hartikainen JM, Chenevix-Trench G, Van Dyck L, Janssen H, Chang-Claude J, Rudolph A, Radice P, Peterlongo P, Hallberg E, Olson JE, Giles GG, Milne RL, Haiman CA, Schumacher F, Simard J, Dumont M, Kristensen V, Borresen-Dale AL, Zheng W, Beeghly-Fadiel A, Grip M, Andrulis IL, Glendon G, Devilee P, Seynaeve C, Hooning MJ, Collée M, Cox A, Cross SS, Shah M, Luben RN, Hamann U, Torres D, Jakubowska A, Lubinski J, Couch FJ, Yannoukakos D, Orr N, Swerdlow A, Darabi H, Li J, Czene K, Hall P, Easton DF, Mattson J, Blomqvist C, Aittomäki K, and Nevanlinna H

Subjects
Breast Neoplasms etiology, DNA-Binding Proteins physiology, Female, Finland, Genetic Predisposition to Disease genetics, Genotyping Techniques, Haplotypes genetics, Heterozygote, Humans, Male, Middle Aged, Mutation, Missense, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Polymorphism, Single Nucleotide genetics
Abstract

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.

Published
2016
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22. [Tick-borne encephalitis in Finland from 2010 to 2012].

Author

Metsi J, Vuorela M, Kantele A, Kuusi M, and Oksi J

Subjects
Disease Progression, Encephalitis, Tick-Borne complications, Europe epidemiology, Female, Finland epidemiology, Humans, Male, Encephalitis, Tick-Borne epidemiology
Abstract

The frequency of occurrence of tick-borne encephalitis has increased significantly in Europe and Finland during the past twenty years. There has been a suspicion that the Finnish cases have at least over the last few years been more severe than described in the literature. We analyzed the approximately one hundred cases of tick-borne encephalitis diagnosed in Finland over a three-year period. In two thirds of the patients general physical condition deteriorated clearly, the disease caused permanent disability or the patients required supportive measures in the hospital, such as ventilator therapy. Assessment of the course and severity of the disease would seem to be impossible on the basis of individual symptoms, such as duration of fever.

Published
2015

23. Bloodstream infections among children with juvenile idiopathic arthritis: a prospective study from the onset of disease.

Author

Salonen PH, Säilä H, Salonen JH, Vuorela M, Kautiainen H, Lyytikäinen O, Kauppi MJ, Leirisalo-Repo M, and Repo H

Subjects
Adolescent, Anti-Bacterial Agents therapeutic use, Antirheumatic Agents therapeutic use, Arthritis, Juvenile diagnosis, Arthritis, Juvenile drug therapy, Bacterial Infections diagnosis, Bacterial Infections drug therapy, Bacterial Infections microbiology, Child, Preschool, Escherichia coli Infections epidemiology, Escherichia coli Infections microbiology, Female, Finland epidemiology, Fusobacteriaceae Infections epidemiology, Fusobacteriaceae Infections microbiology, Humans, Immunosuppressive Agents therapeutic use, Incidence, Male, Pneumococcal Infections epidemiology, Pneumococcal Infections microbiology, Prospective Studies, Registries, Risk Factors, Staphylococcal Infections epidemiology, Staphylococcal Infections microbiology, Time Factors, Treatment Outcome, Arthritis, Juvenile epidemiology, Bacterial Infections epidemiology
Abstract

Objectives: To describe the incidence and nature of bloodstream infections (BSI) among children with juvenile idiopathic arthritis (JIA) followed-up prospectively from disease onset., Methods: The Social Insurance Institution's (SII) national register on individuals with reimbursement for medication of chronic diseases was used to identify children with JIA from 2004 through 2011 and their medications. The National Infectious Disease Register (NIDR) collects data of all blood culture positive samples from all microbiology laboratories in Finland. We combined the NIDR and SII registers to identify JIA patients with BSI. Clinical and laboratory data of each JIA-BSI patient were collected from hospital records., Results: There were 1604 JIA patients and 6630 person-years of follow-up. Five patients had BSI. During the first 5 years after diagnosis the cumulative emergence of BSI was 0.38% [95% confidence interval (CI) 0.16% to 0.92%]. The incidence rates were 7.5/10 000 follow-up years for JIA (95% CI 2.4-17.6) and 2.8/10 000 follow-up years for the age-matched general population (95% CI 2.7-2.9). The standardised incidence ratio was 3.0 (95% CI 1.2 to 7.2). The causative bacteria were Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli and Fusobacterium necrophorum. Three patients were on anti-rheumatic drugs, including two on TNF inhibitors. All patients responded rapidly to antimicrobial therapy and recovered uneventfully., Conclusions: Although BSI is rare among children with JIA, the incidence is 3-fold higher than among the general population.

Published
2014

24. [A domestic human case of hepatitis E in Finland].

Author

Kettunen O, Vuorela M, Kuusi M, Kantala T, Maunula L, Jalava K, Blomster T, Koskela R, and Haapasaari KM

Subjects
Finland, Genotype, Hepatitis E genetics, Humans, Immunoglobulin M blood, Liver Function Tests, Male, Middle Aged, RNA, Viral blood, Hepatitis E diagnosis
Abstract

We describe the first verified domestic HEV case in a previously healthy 53-year-old man who presented a three-day history of upper stomach pain, nausea, fever, arthralgia and fatigue. At the first phase laboratory tests revealed high levels of AST and ALT and at the second phase high levels of bilirubin. Serum was positive for anti-HEV IgM and for HEV RNA confirming the diagnosis of acute hepatitis E. The HEV was genotype 3. Jaundice resolved in three months. In nonendemic areas autochthonous hepatitis E is more common than previously recognized and is possible in patients with acute hepatitis.

Published
2013

25. Rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and TP53 tumor suppression network.

Author

Pylkäs K, Vuorela M, Otsukka M, Kallioniemi A, Jukkola-Vuorinen A, and Winqvist R

Subjects
Adult, Aged, Aged, 80 and over, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms metabolism, Estrogens genetics, Fanconi Anemia Complementation Group N Protein, Female, Humans, Middle Aged, Mutation, Nuclear Proteins genetics, Signal Transduction, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics, Breast Neoplasms genetics, DNA Copy Number Variations, Estrogens metabolism, Tumor Suppressor Protein p53 metabolism
Abstract

Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Published
2012
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26. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.

Author

Vuorela M, Pylkäs K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt Wäppling A, Haanpää M, Puistola U, Rosengren A, Anttila M, Kosma VM, Mannermaa A, and Winqvist R

Subjects
Adolescent, Adult, Aged, Alleles, Base Sequence, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Middle Aged, Pedigree, Young Adult, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics
Abstract

RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13&#95;14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families.

Published
2011
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27. Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families.

Author

Vuorela M, Pylkäs K, and Winqvist R

Subjects
Adult, Aged, Aged, 80 and over, Base Sequence, DNA Mutational Analysis, DNA Primers genetics, DNA, Neoplasm genetics, Female, Finland, Genetic Predisposition to Disease, Genetic Testing, Heterozygote, Humans, Middle Aged, Ubiquitin-Protein Ligases, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Ligases genetics, Ubiquitin-Conjugating Enzymes genetics
Abstract

Background: Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer., Methods: The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing., Results: Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility., Conclusions: The present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.

Published
2011
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28. Mutation analysis of the gene encoding the PALB2-binding protein MRG15 in BRCA1/2-negative breast cancer families.

Author

Rio Frio T, Haanpää M, Pouchet C, Pylkäs K, Vuorela M, Tischkowitz M, Winqvist R, and Foulkes WD

Subjects
Adult, Aged, Aged, 80 and over, Breast Neoplasms epidemiology, DNA Mutational Analysis, Fanconi Anemia Complementation Group N Protein, Female, Genes, BRCA1, Genes, BRCA2, Humans, Middle Aged, Risk, Transcription Factors metabolism, Young Adult, Breast Neoplasms genetics, Genetic Predisposition to Disease, Nuclear Proteins metabolism, Transcription Factors genetics, Tumor Suppressor Proteins metabolism
Abstract

MRG15 is a recently identified member of the BRCA multiprotein complex, essential for the maintenance of the genome integrity and DNA repair. The functional relationship between PALB2 and MRG15 makes MRG15 a strong candidate breast cancer susceptibility gene. We screened affected probands from 232 BRCA1/2-negative breast cancer families for mutations in MRG15. We identified seven previously unreported variants but in silico analyses revealed that none of these variants appears to modify the function of MRG15. Thus, it seems unlikely that any constitutional changes in MRG15 confer an increased risk for breast cancer.

Published
2010
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29. Development of microbial populations in the anaerobic hydrolysis of grass silage for methane production.

Author

Wang H, Vuorela M, Keränen AL, Lehtinen TM, Lensu A, Lehtomäki A, and Rintala J

Subjects
Anaerobiosis, Archaea classification, Archaea genetics, Bacteria classification, Bacteria genetics, Bioreactors, DNA, Archaeal genetics, DNA, Bacterial genetics, Hydrolysis, Phylogeny, Poaceae, Polymorphism, Restriction Fragment Length, RNA, Ribosomal, 16S genetics, Sewage microbiology, Archaea isolation & purification, Bacteria isolation & purification, Methane biosynthesis, Silage microbiology
Abstract

Six batch leach bed (LB) reactors, installed in parallel and connected to a common upflow anaerobic sludge blanket reactor, were fed with grass silage and operated at 35 (+/-1) degrees C. The development and distribution of microorganisms, which firmly and loosely attached to solid materials, and presented in the leachate in the LB reactors, were investigated by 16S rRNA gene-based terminal restriction fragment length polymorphism and clone library analyses. The phylotypes and their relative abundance changed in the respective bacterial community throughout the 49-day run and showed differences between the communities. Large numbers of phylotypes were detected from day 10 onwards. On day 17, the majority of phylotypes in the bacterial community firmly attached to solid residues affiliated to the classes Clostridia and Bacteroidetes. There were high numbers of the phylotypes in the leachate bacterial community. They were closely related to members of classes Clostridia, Bacteroidetes, Betaproteobacteria, Alphaproteobacteria, Gammaproteobacteria, and OP10. The Clostridium-like species clearly dominated the bacterial community. Archaea were only found in the solid residues on day 17 and in the leachate on days 10 and 17. The majority of the Archaea fell within the hydrogenotrophic genus Methanobacterium. The organism assigned to the aceticlastic genus Methanosarcina was only present in the solid residues.

Published
2010
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30. Botulism associated with vacuum-packed smoked whitefish in Finland, June-July 2006.

Author

Lindstrom M, Vuorela M, Hinderink K, Korkeala H, Dahlsten E, Raahenmaa M, and Kuusi M

Subjects
Aged, Animals, Botulism, Disease Outbreaks statistics & numerical data, Female, Finland epidemiology, Humans, Incidence, Population Surveillance, Risk Assessment methods, Risk Factors, Smoke, Clostridium botulinum isolation & purification, Fish Products microbiology, Food Contamination statistics & numerical data, Fruit microbiology, Gastroenteritis epidemiology, Salmonidae microbiology
Published
2006
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