Abstract
Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology.
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International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320
Freimer N, Sabatti C (2003) The human phenome project. Nat Genet 34:15–21
Zbuk KM, Eng C (2007) Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 7:35–45
Fernandez-Ricaud L, Warringer J, Ericson E et al (2007) PROPHECY: a yeast phenome database, update 2006. Nucleic Acids Res 35:D463–467
Grubb SC, Maddatu TP, Bult CJ, Bogue MA (2009) Mouse phenome database. Nucleic Acids Res 37:D720–730
de la Cruz N, Bromberg S, Pasko D et al (2005) The Rat Genome Database (RGD): developments towards a phenome database. Nucleic Acids Res 33:D485–491
Singer E (2005) “Phenome” project set to pin down subgroups of autism. Nat Med 11:583
Groth P, Pavlova N, Kalev I et al (2007) PhenomicDB: a new cross-species genotype/phenotype resource. Nucleic Acids Res 35:D696–699
Johnston PG, Fisher ER, Rockette HE et al (1994) The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12:2640–2647
Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511
van’ t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536
Colhoun HM, McKeigue PM, Davey Smith G (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361:865–872
Editor (1999) Freely associating. Nat Genet 22:1–2
Little J, Higgins JP, Ioannidis JP et al (2009) STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 6:e22
Gambaro G, Anglani F, D’Angelo A (2000) Association studies of genetic polymorphisms and complex disease. Lancet 355:308–311
Nebert DW (2000) Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics. Eur J Pharmacol 410:107–120
Perez-Gracia JL, Ruiz-Ilundain MG (2001) Cancer protective mutations: looking for the needle in the haystack. Clin Transl Oncol 3:169–171
Perez-Gracia JL, Gloria Ruiz-Ilundain M, Garcia-Ribas I, Maria Carrasco E (2002) The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research. Cancer 95:1605–1610
Reichardt JK, Mehrian-Shai R (2009) The future of the human SNP identification: which individuals to sequence? Proc Natl Acad Sci U S A 106:E50
Lin DW, Porter M, Montgomery B (2009) Treatment and survival outcomes in young men diagnosed with prostate cancer: a population-based cohort study. Cancer 115:2863–2871
Online Mendelian Inheritance in Man, OMIM™. Available at http://www.ncbi.nlm.nih.gov/omim/
Erdheim J (1903) Zur normalen und pathologischen Histologie der glandula Thyroidea, Parathyroidea und Hypophysis. Beitr Pathol Anat 33:1–234
Rossier P, Dressler M (1939) Familiare Erkrangung innersekretorischer drusen kombiniert mit Ulcuskrankheit. Schweiz Med Wochenschr 69:985–990
Schmid JR, Labhart A, Rossier PH (1961) Relationship of multiple endocrine adenomas to the syndrome of ulcerogenic islet cell adenomas (Zollinger-Ellison). Occurrence of both syndromes in one family. Am J Med 31:343–353
Larsson C, Skogseid B, Oberg K et al (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85–87
Chandrasekharappa SC, Guru SC, Manickam P et al (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407
Hall JM, Lee MK, Newman B et al (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689
Miller RW (1968) Deaths from childhood cancer in sibs. N Engl J Med 279:122–126
Li FP, Fraumeni JF Jr (1969) Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43:1365–1373
Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238
Tuchman M, Stoeckeler JS, Kiang DT et al (1985) Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med 313:245–249
Diasio RB, Beavers TL, Carpenter JT (1988) Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest 81:47–51
Van Kuilenburg AB, Vreken P, Beex LV et al (1997) Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. Eur J Cancer 33:2258–2264
Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500
Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139
Herbst RS, Prager D, Hermann R et al (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899
Gatzemeier U, Pluzanska A, Szczesna A et al (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced nonsmall-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25:1545–1552
Giaccone G, Herbst RS, Manegold C et al (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial — INTACT 1. J Clin Oncol 22:777–784
Herbst RS, Giaccone G, Schiller JH et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial — INTACT 2. J Clin Oncol 22:785–794
Zhang G, Nebert DW, Chakraborty R, Jin L (2006) Statistical power of association using the extreme discordant phenotype design. Pharmacogenet Genomics 16:401–413
Silberstein E, Walfisch S, Lupu L, Sztarkier I (2000) Twelve-year survival after the diagnosis of locally advanced carcinoma of the pancreas: a case report. J Surg Oncol 75:142–145
Spinelli GP, Zullo A, Romiti A et al (2006) Longterm survival in metastatic pancreatic cancer. A case report and review of the literature. JOP 7:486–491
Miyaji M, Ogoshi K, Kajiura Y et al (1996) [A case of advanced gastric cancer with liver metastasis with no recurrence and long survival]. Gan To Kagaku Ryoho 23:915–918
Shibata N, Tamai M, Ikeda K (1995) [Case report of long-term survivor of advanced gastric cancer associated with peritoneal dissemination successfully treated with cancer chemotherapy]. Gan To Kagaku Ryoho 22:119–122
Fukasawa T, Shoji T, Gotoh H, Taniwaka K (2006) [A long-term survivor with stage IV gastric cancer due to postoperative weekly paclitaxel and 5′-DFUR combination therapy]. Gan To Kagaku Ryoho 33:235–238
Wada T, Iwanaga T, Koyama H et al (1988) [A case report of long-term survival in advanced gastric cancer with multiple liver metastases treated with mitomycin C and tegafur therapy after palliative gastrectomy]. Gan To Kagaku Ryoho 15:353–356
Mukai M, Tokunaga N, Yasuda S et al (2000) Long-term survival after immunochemotherapy for juvenile colon cancer with peritoneal dissemination: a case report. Oncol Rep 7:1343–1347
Seto T, Seto M, Ono K et al (2000) [A long-term survivor of extensive-stage small cell lung cancer]. Gan To Kagaku Ryoho 27:135–138
Mall JW, Philipp AW, Mall W, Pollmann C (2002) Long-term survival of a patient with small-cell lung cancer (SCLC) following treatment with thalidomide and combination chemotherapy. Angiogenesis 5:11–13
Izumi Y, Mukai M, Kikuchi K, Kobayashi K (2006) Long-term survival after incomplete resection of immunohistochemically diagnosed T0N1 lung cancer: report of a case. Surg Today 36:270–273
Mac Manus MP, Matthews JP, Wada M et al (2006) Unexpected long-term survival after low-dose palliative radiotherapy for non-small cell lung cancer. Cancer 106:1110–1116
Dutcher JP, Wiernik PH (1984) Long-term survival of a patient with multiple myeloma: a cure? A case report. Cancer 53:2069–2072
Yamshchikov GV, Mullins DW, Chang CC et al (2005) Sequential immune escape and shifting of T cell responses in a long-term survivor of melanoma. J Immunol 174:6863–6871
Le Gal FA, Widmer VM, Dutoit V et al (2007) Tissue homing and persistence of defined antigenspecific CD8+ tumor-reactive T-cell clones in long-term melanoma survivors. J Invest Dermatol 127:622–629
Yamshchikov G, Thompson L, Ross WG et al (2001) Analysis of a natural immune response against tumor antigens in a melanoma survivor: lessons applicable to clinical trial evaluations. Clin Cancer Res 7:909s–916s
Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148
Perez-Gracia JL, Prior C, Guillen-Grima F et al (2009) Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array. Br J Cancer 101:1876–1883
Sabatino M, Kim-Schulze S, Panelli MC et al (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27:2645–2652
Liu R, Paxton WA, Choe S et al (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367–377
Quillent C, Oberlin E, Braun J et al (1998) HIV-1- resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene. Lancet 351:14–18
Rowland-Jones S, Sutton J, Ariyoshi K et al (1995) HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med 1:59–64
Garcia-Cao I, Garcia-Cao M, Martin-Caballero J et al (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21:6225–6235
Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021
Cui Z, Willingham MC, Hicks AM et al (2003) Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice. Proc Natl Acad Sci U S A 100:6682–6687
Black WC, Welch HG (1993) Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med 328:1237–1243
Belogubova EV, Togo AV, Karpova MB et al (2004) A novel approach for assessment of cancer predisposing roles of GSTM1 and GSTT1 genes: use of putatively cancer resistant elderly tumor-free smokers as the referents. Lung Cancer 43:259–266
Belogubova EV, Kuligina E, Togo AV et al (2005) ’Comparison of extremes’ approach provides evidence against the modifying role of NAT2 polymorphism in lung cancer susceptibility. Cancer Lett 221:177–183
Belogubova EV, Ulibina YM, Suvorova IK et al (2006) Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects. J Cancer Res Clin Oncol 132:327–331
Belogubova EV, Togo AV, Kondratieva TV et al (2000) GSTM1 genotypes in elderly tumour-free smokers and non-smokers. Lung Cancer 29:189–195
Collins FS, Green ED, Guttmacher AE, Guyer MS (2003) A vision for the future of genomics research. Nature 422:835–847
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Pérez-Gracia, J.L., Gúrpide, A., Ruiz-Ilundain, M.G. et al. Selection of extreme phenotypes: the role of clinical observation in translational research. Clin Transl Oncol 12, 174–180 (2010). https://doi.org/10.1007/s12094-010-0487-7
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DOI: https://doi.org/10.1007/s12094-010-0487-7