Breast Cancer Susceptibility and the DNA Damage Response

Miki Y. , Swensen J. , Shattuck-Eidens D. . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266: 66–71.

Tavtigian S.V. , Simard J. , Rommens J. . The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996; 12: 333–337.

Ford D. , Easton D.F. , Stratton M. . Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998; 62: 676–689.

Peto J. , Collins N. , Barfoot R. . Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999; 91: 943–949.

Serova O.M. , Mazoyer S. , Puget N. . Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997; 60: 486–495.

Balmain A. , Gray J. , Ponder B. . The genetics and genomics of cancer. Nat Genet. 2003; 33(suppl): 238–244.

Kainu T. , Juo S.H. , Desper R. . Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc Natl Acad Sci U S A. 2000; 97: 9603–9608.

Thompson D. , Szabo C.I. , Mangion J. . Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci U S A. 2002; 99: 827–831. Epub 2002.

Antoniou A.C. , Easton D.F. . Polygenic inheritance of breast cancer: implications for design of association studies. Genet Epidemiol. 2003; 25: 190–202.

de Jong M.M. , Nolte I.M. , te Meerman G.J. . Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet. 2002; 39: 225–242

Martin A.M. , Weber B.L. . Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst. 2000; 92: 1126–1135.

Narod S.A. , Foulkes W.D. . BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004; 4: 665–676.

Khanna K.K. , Jackson S.P. . DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27: 247–254.

Pierce A.J. , Stark J.M. , Araujo F.D. . Double-strand breaks and tumorigenesis. Trends Cell Biol. 2001; 11: S52–S59.

Futreal P.A. , Liu Q. , Shattuck-Eidens D. . BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994; 266: 120–122.

Lancaster J.M. , Wooster R. , Mangion J. . BRCA2 mutations in primary breast and ovarian cancers. Nat Genet. 1996; 13: 238–240.

Venkitaraman A.R. . Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002; 108: 171–182.

Boulton S.J. , Martin J.S. , Polanowska J. . BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans. Curr Biol. 2004; 14: 33–39.

Moynahan M.E. , Chiu J.W. , Koller B.H. . BRCA1 controls homology-directed DNA repair. Mol Cell. 1999; 4: 511–518.

Abbott D.W. , Thompson M.E. , Robinson-Benion C. . BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem. 1999; 274: 18808–18812.

Wang H. , Zeng Z.C. , Bui T.A. . Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2. Cancer Res. 2001; 61: 270–277.

Scully R. , Xie A. , Nagaraju G. . Molecular Functions of BRCA1 in the DNA Damage Response. Cancer Biol Ther. 2004; 3: 521–527. Epub 2004.

Patel K.J. , Yu V.P. , Lee H. . Involvement of Brca2 in DNA repair. Mol Cell. 1998; 1: 347–357.

Ban S. , Shinohara T. , Hirai Y. . Chromosomal instability in BRCA1-or BRCA2-defective human cancer cells detected by spontaneous micronucleus assay. Mutat Res. 2001; 474: 15–23.

Scully R. , Livingston D.M. . In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 2000; 408: 429–432.

Kerr P. , Ashworth A. . New complexities for BRCA1 and BRCA2. Curr Biol. 2001; 11: R668–676.

Zhou B.B. , Elledge S.J. . The DNA damage response: putting checkpoints in perspective. Nature. 2000; 408: 433–439.

Scully R. , Chen J. , Plug A. . Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997; 88: 265–275.

Zhong Q. , Chen C.F. , Li S. . Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science. 1999; 285: 747–750.

BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000; 14: 927–939.

Bochar D.A. , Wang L. , Beniya H. . BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell. 2000; 102: 257–265.

Ye Q. , Hu Y.F. , Zhong H. . BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 2001; 155: 911–921. Epub 2001 Dec 10.

Pao G.M. , Janknecht R. , Ruffner H. . CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc Natl Acad Sci U S A. 2000; 97: 1020–1025.

Yarden R.I. , Brody L.C. . BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci U S A. 1999; 96: 4983–4988.

Cantor S.B. , Bell D.W. , Ganesan S. . BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001; 105: 149–160.

Davies A.A. , Masson J.Y. , McIlwraith M.J. . Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 2001; 7: 273–282.

Chen P.L. , Chen C.F. , Chen Y. . The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A. 1998; 95: 5287–5292.

Savitsky K. , Sfez S. , Tagle D.A. . The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet. 1995; 4: 2025–2032.

Khanna K.K. . Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst. 2000; 92: 795–802.

Swift M. , Morrell D. , Massey R.B. . Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991; 325: 1831–1836.

Geoffroy-Perez B. , Janin N. , Ossian K. . Cancer risk in heterozygotes for ataxia-telangiectasia. Int J Cancer. 2001; 93: 288–293.

Olsen J.H. , Hahnemann J.M. , Borresen-Dale A.L. . Cancer in patients with ataxia-telangiectasia and in their relatives in the Nordic countries. J Natl Cancer Inst. 2001; 93: 121–127.

Telatar M. , Teraoka S. , Wang Z. . Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998; 62: 86–97.

FitzGerald M.G. , Bean J.M. , Hegde S.R. . Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997; 15: 307–310.

Gatti R.A. , Tward A. , Concannon P. . Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab. 1999; 68: 419–423.

Chenevix-Trench G. , Spurdle A.B. , Gatei M. . Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst. 2002; 94: 205–215. Erratum in: J Natl Cancer Inst. 2002;94: 952.

Spring K. , Ahangari F. , Scott S.P. . Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet. 2002; 32: 185–190. Epub 2002 Aug 26.

Bakkenist C.J. , Kastan M.B. . DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003; 421: 499–506.

Garber J.E. , Goldstein A.M. , Kantor A.F. . Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 1991; 51: 6094–6097.

Malkin D. , Li F.P. , Strong L.C. . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250: 1233–1238. Erratum in: Science. 1993;259: 878.

Easton D.F. , Bishop D.T. , Ford D. . Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993; 52: 678–701.

Vogelstein B. , Lane D. , Levine A.J. . Surfing the p53 network. Nature. 2000; 408: 307–310.

Gasco M. , Yulug I.G. , Crook T. . TP53 mutations in familial breast cancer: functional aspects. Hum Mutat. 2003; 21: 301–306.

Crook T. , Crossland S. , Crompton M.R. . p53 mutations in BRCA1-associated familial breast cancer. Lancet. 1997; 350: 638–639.

Smith P.D. , Crossland S. , Parker G. . Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene. 1999; 18: 2451–2459.

Pharoah P.D. , Day N.E. , Caldas C. . Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer. 1999; 80: 1968–1973.

Bell D.W. , Varley J.M. , Szydlo T.E. . Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999; 286: 2528–2531.

Matsuoka S. , Huang M. , Elledge S.J. . et al. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998; 282: 1893–1897.

Matsuoka S. , Rotman G. , Ogawa A. . Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci U S A. 2000; 97: 10389–10394.

Chehab N.H. , Malikzay A. , Appel M. . Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 2000; 14: 278–288.

Shieh S.Y. , Ahn J. , Tamai K. . The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 2000; 14: 289–300. Erratum in: Genes Dev. 2000;14: 750.

Lee J.S. , Collins K.M. , Brown A.L. . hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000; 404: 201–204.

Meijers-Heijboer H. , van den Ouweland A. , Klijn J. . Low-penetrance susceptibility to breast cancer due to CHEK2(∗)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002; 31: 55–59. Epub 2002 Apr 22.

Vahteristo P. , Bartkova J. , Eerola H. . A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002; 71: 432–438. Epub 2002 Jul 28.

Schutte M. , Seal S. , Barfoot R. . Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet. 2003; 72: 1023–8. Epub 2003 Feb 27.

Oldenburg R.A. , Kroeze-Jansema K. , Kraan J. . The CHEK2∗1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. 2003; 63: 8153–8157.

Li J. , Yen C. , Liaw D. . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275: 1943–1947.

Steck P.A. , Pershouse M.A. , Jasser S.A. . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15: 356–362.

Liaw D. , Marsh D.J. , Li J. . Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997; 16: 64–67.

Nelen M.R. , van Staveren W.C. , Peeters E.A. . Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997; 6: 1383–1387.

Tsou H.C. , Teng D.H. , Ping X.L. . The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet. 1997; 61: 1036–1043.

Marsh D.J. , Kum J.B. , Lunetta K.L. . PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999; 8: 1461–1472.

Eng C. , Peacocke M. . PTEN and inherited hamartoma-cancer syndromes. Nat Genet. 1998; 19: 223.

Feilotter H.E. , Coulon V. , McVeigh J.L. . Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer. 1999; 79: 718–723.

Teng D.H. , Hu R. , Lin H. . MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 1997; 57: 5221–5225.

Singh B. , Ittmann M.M. , Krolewski J.J. . Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosomes Cancer. 1998; 21: 166–171.

Maehama T. , Dixon J.E. . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273: 13375–13378.

Rena G. , Guo S. , Cichy S.C. . Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999; 274: 17179–17183.

Nakamura N. , Ramaswamy S. , Vazquez F. . Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol. 2000; 20: 8969–8982.

Tran H. , Brunet A. , Grenier J.M. . DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002; 296: 530–534.

Monteiro A.N. . BRCA1: the enigma of tissue-specific tumor development. Trends Genet. 2003; 19: 312–315.

Elledge S.J. , Amon A. . The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients. Cancer Cell. 2002; 1: 129–132.

Sigurdson A.J. , Hauptmann M. , Chatterjee N. . Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes. BMC Cancer. 2004; 4: 9.

Rutter J.L. , Smith A.M. , Davila M.R. . Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Hum Mutat. 2003; 22: 121–128.

Karppinen S.M. , Vuosku J. , Heikkinen K. . No evidence of involvement of germline BACH1 mutations in Finnish breast and ovarian cancer families. Eur J Cancer. 2003; 39: 366–371.

Luo L. , Lei H. , Du Q. . No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast-cancer families linked to 17q22. Int J Cancer. 2002; 98: 638–639

Karppinen S.M. , Heikkinen K. , Rapakko K. , Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J Med Genet. 2004; 41: e114.

Thai T.H. , Du F. , Tsan J.T. . Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet. 1998; 7: 195–202.

Ghimenti C. , Sensi E. , Presciuttini S. . Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer. 2002; 33: 235–242.

Ishitobi M. , Miyoshi Y. , Hasegawa S. . Mutational analysis of BARD1 in familial breast cancer patients in Japan. Cancer Lett. 2003; 200: 1–7.

Fu Y.P. , Yu J.C. , Cheng T.C. . Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res. 2003; 63: 2440–2446.

Sensi E. , Tancredi M. , Aretini P. . Clinicopathological significance of GADD45 gene alterations in human familial breast carcinoma. Breast Cancer Res Treat. 2004; 87: 197–201.

Monteiro A.N. , Zhang S. , Phelan C.M. , Absence of constitutional H2AX gene mutations in 101 hereditary breast cancer families. J Med Genet. 2003; 40: e51.

Kuschel B. , Auranen A. , McBride S. . Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet. 2002; 11: 1399–1407.

Han J. , Hankinson S.E. , Ranu H. . Polymorphisms in DNA double-strand break repair genes and breast cancer risk in the Nurses’ Health Study. Carcinogenesis. 2004; 25: 189–195. Epub 2003 Oct 24.

Heikkinen K. , Karppinen S.M. , Soini Y. . Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J Med Genet. 2003; 40: e131.

Forsti A. , Angelini S. , Festa F. . Single nucleotide polymorphisms in breast cancer. Oncol Rep. 2004; 11: 917–922.

Steffen J. , Varon R. , Mosor M. . Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer. 2004; 111: 67–71.

Gorski B. , Debniak T. , Masojc B. . Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int J Cancer. 2003; 106: 379–381. Erratum in: Int J Cancer. 2003;106: 984.

Kato M. , Yano K. , Matsuo F. . Identification of Rad51 alteration in patients with bilateral breast cancer. J Hum Genet. 2000; 45: 133–137.

Bell D.W. , Wahrer D.C. , Kang D.H. . Common nonsense mutations in RAD52. Cancer Res. 1999; 59: 3883–3888.

Levy-Lahad E. , Lahad A. , Eisenberg S. . A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A. 2001; 98: 3232–3236.

Kadouri L. , Kote-Jarai Z. , Hubert A. . A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer. 2004; 90: 2002–2005.

Jakubowska A. , Narod S.A. , Goldgar D.E. . Breast cancer risk reduction associated with the RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland. Cancer Epidemiol Biomarkers Prev. 2003; 12: 457–459.

Wang W.W. , Spurdle A.B. , Kolachana P. . A single nucleotide polymorphism in the 5’ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2001; 10: 955–960.

Tong D. , Volm T. , Eberhardt E. . Rad52 gene mutations in breast/ovarian cancer families and sporadic ovarian carcinoma patients. Oncol Rep. 2003; 10: 1551–1553.

Han J. , Hankinson S.E. , De Vivo I. . No association between a stop codon polymorphism in RAD52 and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2002; 11 (10 pt 1): 1138–1139.

Matsuda M. , Miyagawa K. , Takahashi M. . Mutations in the RAD54 recombination gene in primary cancers. Oncogene. 1999; 18: 3427–3430.

Smith T.R. , Levine E.A. , Perrier N.D. . DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2003; 12 (11 pt 1): 1200–1204.

Kumar R. , Hoglund L. , Zhao C. . Single nucleotide polymorphisms in the XPG gene: determination of role in DNA repair and breast cancer risk. Int J Cancer. 2003; 103: 671–675.

Moullan N. , Cox D.G. , Angele S. . Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy. Cancer Epidemiol Biomarkers Prev. 2003; 12 (11 pt 1): 1168–1174.

Duell E.J. , Millikan R.C. , Pittman G.S. . Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomarkers Prev. 2001; 10: 217–222.

Shu X.O. , Cai Q. , Gao Y.T. . A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2003; 12: 1462–1467.

Smith T.R. , Miller M.S. , Lohman K. . Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. Cancer Lett. 2003; 190: 183–190.

Figueiredo J.C. , Knight J.A. , Briollais L. . Polymorphisms XRCC1-R399Q and XRCC3-T241M and the risk of breast cancer at the Ontario site of the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2004; 13: 583–591.

Rodriguez-Lopez R. , Osorio A. , Sanchez-Pulido L. . No mutations in the XRCC2 gene in BRCA1/2-negative high-risk breast cancer families. Int J Cancer. 2003; 103: 136–137.

Rafii S. , O'Regan P. , Xinarianos G. . A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet. 2002; 11: 1433–1438.

Jacobsen N.R. , Nexo B.A. , Olsen A. . No association between the DNA repair gene XRCC3 T241M polymorphism and risk of skin cancer and breast cancer. Cancer Epidemiol Biomarkers Prev. 2003; 12: 584–585.

Goode E.L. , Ulrich C.M. , Potter J.D. . Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 2002; 11: 1513–1530.

van Haaften G. , Vastenhouw N.L. , Nollen E.A. . Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality. Proc Natl Acad Sci U S A. 2004; 101: 12992–12996. Epub 2004 Aug 23.

Marnellos G. . High-throughput SNP analysis for genetic association studies. Curr Opin Drug Discov Devel. 2003; 6: 317–321.

Kirk B.W. , Feinsod M. , Favis R. . Single nucleotide polymorphism seeking long term association with complex disease. Nucleic Acids Res. 2002; 30: 3295–3311.