Research in the Tavtigian Lab concentrates on two areas of genetic susceptibility to cancer. The first is identification and characterization of intermediate-risk and high-risk cancer susceptibility genes. The second is analysis of unclassified variants that are observed during the clinical testing of established high-risk cancer susceptibility genes.
Historically, most of the known high-risk cancer susceptibility genes were found either by linkage analysis/positional cloning or by mutation screening of established high-risk susceptibility genes' biochemical pathway "nearest neighbors." While the linkage analysis/positional cloning approach is nearly obsolete, next-generation sequencing enables a number of new strategies for gene identification. One of these is whole-exome mutation screening in pedigrees as a method to identify relatively high-risk susceptibility genes. Another is biochemical pathway–based mutation screening in a case-control format as a method to identify intermediate-risk susceptibility genes. We are pursuing breast cancer genetics projects in both of these areas and are likely to expand to prostate cancer or colon cancer projects in the near future.
Clinical mutation screening of high-risk cancer susceptibility genes such as BRCA1, BRCA2, MLH1, and MSH2 will often find clearly pathogenic mutations, providing very useful information for the clinical management of high-risk patients and their close relatives. However, about 10% of patients who undergo mutation screening are found to carry an unclassified sequence variant (UV). Observations of UVs are problematic for clinical mutation screening services, for clinical cancer genetics, and for the patients. We have developed a bioinformatics method, called the "integrated evaluation," for analysis and eventual classification of UVs. Currently, the method is applicable to UVs in the breast cancer susceptibility genes BRCA1 and BRCA2. We are working to improve the method, to extend it to other susceptibility genes, and to create databases that will disseminate classification results to clinical cancer geneticists throughout the world.
- Tavtigian SV, Greenblatt MS, Harrison SM, Nussbaum RL, Prabhu SA, Boucher KM, Biesecker LG (2018). Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.LID - 10.1038/gim.2017.210 [doi]. (Epub ahead of print) Genet Med.
- Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, John EM, Hashibe M, Gertz J, Le Calvez-Kelm F, Lesueur F, Goldgar DE, Tavtigian SV (2016). Multigene testing of moderate-risk genes: be mindful of the missense. J Med Genet, 53(6), 366-76.
- Vallee MP, Di Sera TL, Nix DA, Paquette AM, Parsons MT, Bell R, Hoffman A, Hogervorst FB, Goldgar DE, Spurdle AB, Tavtigian SV (2016). Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants. Hum Mutat, 37(7), 627-39.
- Samadder NJ, Neklason DW, Boucher KM, Byrne KR, Kanth P, Samowitz W, Jones D, Tavtigian SV, Done MW, Berry T, Jasperson K, Pappas L, Smith L, Sample D, Davis R, Topham MK, Lynch P, Strait E, McKinnon W, Burt RW, Kuwada SK (2016). Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial. JAMA, 315(12), 1266-75.
- Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F, Odefrey F, Tsimiklis H, Teo ZL, Thingholm LB, Young EL, Voegele C, Lonie A, Pope BJ, Roane TC, Bell R, Hu H, Shankaracharya, Huff CD, Ellis J, Li J, Makunin IV, John EM, Andrulis IL, Terry MB, Daly M, Buys SS, Snyder C, Lynch HT, Devilee P, Giles GG, Hopper JL, Feng BJ, Lesueur F*, Tavtigian SV*, Southey MC*, Goldgar DE*. (2014) Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers. Cancer Discov. 4(7):804-15. * These authors contributed equally to the work
- Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, Martins A, Moller P, Morak M, Nystrom M, Peltomaki P, Pineda M, Qi M, Ramesar R, Rasmussen LJ, Royer-Pokora B, Scott RJ, Sijmons R, Tavtigian SV, Tops CM, Weber T, Wijnen J, Woods MO, Macrae F, Genuardi M; InSiGHT. (2014) Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 46(2):107-15.
- Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV. (2013) Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. Hum Mutat. 34(1):255-65.
- Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A; Breast Cancer Family Registry; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC. (2012) Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 90(4):734-9.
- Vallée MP, Francy TC, Judkins MK, Babikyan D, Lesueur F, Gammon A, Goldgar DE, Couch FJ, Tavtigian SV. (2012) Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat. 33(1):22-8.
- Tavtigian SV, Hashibe M, Thomas A. (2011) Tests of association for rare variants: case control mutation screening. Nat Rev Genet. 12(3):224.
- Le Calvez-Kelm F, Lesueur F, Damiola F, Vallée M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB; Breast Cancer Family Registry, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV. (2011) Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 13(1):R6.
- Garritano S, Gemignani F, Palmero EI, Olivier M, Martel-Planche G, Le Calvez-Kelm F, Brugiéres L, Vargas FR, Brentani RR, Ashton-Prolla P, Landi S, Tavtigian SV, Hainaut P, Achatz MI. (2010) Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Hum Mutat. 31(2):143-50.
- Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, Lesueur F, Byrnes GB, Chuang SC, Forey N, Feuchtinger C, Gioia L, Hall J, Hashibe M, Herte B, McKay-Chopin S, Thomas A, Vallée MP, Voegele C, Webb PM, Whiteman DC; Australian Cancer Study; Breast Cancer Family Registries (BCFR); Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab), Sangrajrang S, Hopper JL, Southey MC, Andrulis IL, John EM, Chenevix-Trench G. (2009) Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 85(4):427-46.
- Nguyen-Dumont T, Calvez-Kelm FL, Forey N, McKay-Chopin S, Garritano S, Gioia-Patricola L, De Silva D, Weigel R, Sangrajrang S, Lesueur F, Tavtigian SV; Breast Cancer Family Registries (BCFR); Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). (2009) Description and validation of high-throughput simultaneous genotyping and mutation scanning by high-resolution melting curve analysis. Hum Mutat. 30(6):884-90.
- Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A. (2008) Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum Mutat. 29(11):1342-54.
- Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, Hogervorst FB, Hoogerbrugge N, Spurdle AB, Tavtigian SV; IARC Unclassified Genetic Variants Working Group. (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 29(11):1282-91.
- Goldgar DE, Easton DF, Deffenbaugh AM, Monteiro AN, Tavtigian SV, Couch FJ; Breast Cancer Information Core (BIC) Steering Committee. (2004) Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet. 75(4):535-44.
- Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV. (1997) Identification of a candidate tumour suppressor gene, MMAC1†, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 15(4):356-62. †MMAC1 is PTEN
- Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Mitchell JT, McArthur-Morrison J, Nguyen K, Peng Y, Samson C, Schroeder M, Snyder SC, Steele L, Stringfellow M, Stroup C, Swedlund B, Swense J, Teng D, Thomas A, Tran T, Tranchant M, Weaver-Feldhaus J, Wong AK, Shizuya H, Eyfjord JE, Cannon-Albright L, Tranchant M, Labrie F, Skolnick MH, Weber B, Kamb A, Goldgar DE. (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 12(3):333-7.