The new biology: histopathology
1999; Elsevier BV; Volume: 354; Linguagem: Inglês
10.1016/s0140-6736(99)90246-5
ISSN1474-547X
Autores Tópico(s)Cancer Genomics and Diagnostics
ResumoThe new biology will encompass a combination of novel genomic and proteomic data, advances in analysis (eg, nucleic-acid arrays), computation, bioinformatics, and new methods of microscopy and signal localisation. The human genome may be available before the end of the year 2000 and will be rapidly followed by single nucleotide polymorphism sites (SNPS) that can identify points of variation between individuals. These data and the new techniques will have an impact on all areas of medicine.How will these changes affect histopathology? Pathology, the study of disease, and the basis of clinical medicine and many of the fundamental processes underlying human disease, should yield to the tools of the new biology. Histopathology, the study of pathological processes in tissues, is well placed to benefit from such information. DNA and RNA can be analysed from haematoxylin and eosin sections, from fresh tissue or archival paraffin-embedded material, and from samples obtained at surgery, biopsy, cytopathology, or necropsy,1Jackson DP Bell S Payne J et al.Extraction and amplification of DNA from archival haematoxylin and eosin sections and cervical cytology Papanicolaou smears.Nucleic Acids Res. 1989; 17: 101-134Crossref Scopus (18) Google Scholar, 2Jackson DP Hayden JD Quirke P The extraction of nucleic acid from archival material.in: McPherson MJ Quirke P Taylor GR PCR: a practical approach. IRL Press, Oxford1991: 29-50Google Scholar DNA and RNA sequences can be localised in tissues by sensitive in-situ techniques, such as in-situ hybridisation and in-situ PCR amplification, and the tissue distribution of proteins can be simply and rapidly localised by immunocytochemistry. Many of the new techniques can probably be applied to archival material. Archival material has several advantages; not only is it from individuals for whom the disease process has been documented, but also data may be available about the outcome as well as the response to treatment and any associated diseases. Material available from well-controlled clinical trials would enable a wide range of hypotheses to be tested. Histopathology is a biological Klondike.Before our colleagues decide to plan their early retirements, we must also remember that current molecular techniques reduce complex tissue phenotypes into simple stretches of DNA and RNA. Pathological processes are composed of many cell types and these may be in different stages of differentiation. Most molecular techniques "average out" the biological processes rather than identifying specific lesions in the cell lineage of interest. We must accept that in many situations the information from the new biology may not yield as much knowledge as that provided by expert morphological assessment. The new biology will only replace the microscope if the knowledge it yields is more valuable and more cost-effective.The new biology will affect all areas of histopathology, including cytopathology and forensic pathology.HistopathologyThe new biology is starting to have an impact clinically on the histopathology subspecialities. The greatest effects have been in the areas of cancer, infection, and genetics.CancerDiagnosis and classification of tumoursThe new biology is challenging our fundamental pathological concepts of early neoplasia. When does a reactive proliferation become a tumour? Is it the presence of a defined morphological pattern, the excess growth of a particular clone of cells (clonality), or a specific molecular lesion? Can an individual molecular lesion define a neoplasm?The use of molecular techniques raises many difficulties in the early stages of neoplasia. We can identify abnormal clones of cells in morphologically normal mucosa as well as in metaplastic and dysplastic areas.3Chung GT Sunderasan V Hasleton P Rudd R Taylor R Rabbitts P Sequential molecular changes in lung cancer development.Oncogene. 1995; 11: 2591-2598PubMed Google Scholar, 4Ogden GR Hall PA Field change, clonality and early epithelial cancer: possible lessons from p53.J Pathol. 1997; 181: 127-129Crossref PubMed Google Scholar Lesions at the cellular level can also be found in endometriosis,5Jiang X Hitchcock A Bryan EJ et al.Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumour suppressor gene loci.Cancer Res. 1996; 56: 3534-3539PubMed Google Scholar in normal breast tissue,6Deng G Lu Y Zlotnikov G Thor AD Smith HS Loss of heterozygosity in normal tissue adjacent to breast carcinoma.Science. 1996; 274: 2057-2059Crossref PubMed Scopus (492) Google Scholar, 7Larson PS Morenas A Cupples LA Huang K Rosenberg CL Genetically abnormal clones in histologically normal breast tissue.Am J Pathol. 1998; 152: 1591-1598PubMed Google Scholar and in non-neoplastic mucosa from patients with ulcerative colitis,8Brentall TA Crispin DA Bronner MP et al.Microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis.Cancer Res. 1996; 56: 1237-1240PubMed Google Scholar Tissue from the latter group of patients can even show gross abnormalities of DNA content on flow cytometry9Fozard JBJ Quirke P Dixon MF Giles GR Bird CC DNA aneuploidy in ulcerative colitis.Gut. 1986; 27: 1414-1418Crossref PubMed Scopus (72) Google Scholar before the appearance of dysplasia. Indeed both clonality and molecular lesions have been shown in endometriosis which is not deemed a neoplastic process.5Jiang X Hitchcock A Bryan EJ et al.Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumour suppressor gene loci.Cancer Res. 1996; 56: 3534-3539PubMed Google Scholar, 10Tamura M Fukaya T Murakami T Uehara S Yajima A Analysis of clonality in human endometriotic cysts based on evaluation of X-chromosome inactivation in archival formalin-fixed, paraffin-embedded tissue.Lab Invest. 1988; 78: 213-218Google ScholarThe finding of early genetic changes in histologically normal mucosa and non-neoplastic disorders should contain clinically useful information about the development of early neoplasia. Are genetic lesions alone enough to define the neoplastic state? A single mutation in an oncogene such as Kirsten ras can be found in simple non-neoplastic normal mucosa,11Minamoto T Yamashita N Ochiai A et al.Mutant K-ras in apparently normal mucosa of colorectal cancer patients: its potential as a biomarker of colorectal tumorigenesis.Cancer. 1995; 75: 1520-1526Crossref PubMed Scopus (64) Google Scholar colonic metaplastic polyps, and aberrant crypt foci12Nucci MR Robinson CR Longo P Campbell P Hamilton SR Phenotypic and genotypic characteristics of aberrant crypt foci in human colorectal mucosa.Hum Pathol. 1997; 28: 1396-1407Summary Full Text PDF PubMed Scopus (120) Google Scholar as well as neoplastic adenomas and colorectal carcinomas. Inactivation of one copy of a tumour-suppressor gene occurs in all cells in patients with diseases such as hereditary retinoblastoma or familial adenomatous polyposis. Thus, one lesion does not appear to be enough. It takes a second hit to inactivate both copies of a tumour-suppressor gene and initiate carcinogenesis—but how many other lesions have to occur before there is a true neoplasm? Such questions cannot be answered yet but improved understanding of these processes will be provided by the new biology. We will probably have to revise our concepts of early neoplasia in the light of such data.Tumour classification needs substantial amendment in certain areas. Chromosomal and molecular definitions are already used to classify lymphomas, soft-tissue tumours, and paediatric tumours (panel 1) and include such disparate entities as Ewing's sarcoma, Askin tumour, and primitive neuroectodermal tumours (PNET). For these tumours, the identification of a certain translocation defines the type of tumour and thus its therapy. This practice will probably become commonplace; current applications in soft-tissue pathology have been reviewed.13Busam KJ Fletcher CDM The clinical role of molecular genetics in soft tissue tumor pathology.Cancer Metastasis Rev. 1997; 16: 207-227Crossref PubMed Scopus (24) Google Scholar, 14Mentzel T Fletcher CD Recent advances in soft tissue tumor diagnosis.Am J Clin Pathol. 1998; 110: 660-670PubMed Google Scholar, 15de Saint Aubain Somerhausen N Fletcher CD Soft-tissue sarcomas: an update.Eur J Surg Oncol. 1999; 25: 215-220Summary Full Text PDF PubMed Scopus (30) Google Scholar However, these tumours are rare and are a small part of the workload of a district hospital.Panel 1Known translocations that can define leukaemlas and tumoursTabled 1DiseaseTranslocationChrome myelogenous leukaemiaBCR-ABL positiveAtypical chronic myelogenous leukaemiaBCR-ABL negativeAcute myetoid leukaemiaCBF α-ETO, CBF β-MYH11, PML/RAR αLymphoblastic leukaemia/lymphomasBCR/ABL, E2A/PBX1, ETV CBF αEwing's sarcoma, PNET, Askin tumourEWS-FLI-1Extraskeletal myxoid ehondrosarcomaEWS-WT1/ATF1/TECSynovial sarcomaSYT-SSX1/SSX2Myxoid liposarcomaTLS-CHOPAlveolar rhabdomyosarcomaPAX3-FKHR, PAX7-FKHRPNET=primitive neuroectodermal tumour Open table in a new tab What about common tumours? Interesting surprises are turning up even here. A new subtype of a common cancer with a different molecular mechanism and a different clinical behaviour has been described: the cancer due to a defect in mismatch repair.16Boland CR Thibodeau SN Hamilton SR et al.A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. 7th edn. Cancer Res. 58. 1998: 5248-5257Google Scholar These tumours probably have a common underlying abnormality that leads to methylation of the promoter of hMLH-1, a key gene in the repair of small DNA mismatches.17Ahuja N Mohan AL Li Q et al.Association between CpG island methylation and microsatellite instability in colorectal cancer.Cancer Res. 1997; 57: 3370-3374PubMed Google Scholar, 18Herman JG Umar A Polyak K et al.Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.in: 7th edn. Proc Natl Acad Sci USA. 95. 1998: 6870-6875Google Scholar Methylation of the promoter stops production of the protein, induces a failure of mismatch repair, and expansions and contractions of repetitive sequences occur. This causes inactivation of a different pattern of tumour-suppressor genes to that found in the more common p53 pathway (panel 2). These tumours occur in the colon (15%), stomach (10-15%), ovary (3%), endometrium (9-22%), and at other sites.16Boland CR Thibodeau SN Hamilton SR et al.A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. 7th edn. Cancer Res. 58. 1998: 5248-5257Google Scholar Tumours due to defects in mismatch repair may behave differently from those due to other mutations. In colorectal cancer, they have a different distribution (generally located in the right colon), a characteristic histological phenotype (mucinous or poorly differentiated), and an increased frequency of multiple, synchronous, and metachronous cancers, and they may have a better prognosis and respond differently to chemotherapy in vitro.19Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut (in press).Google Scholar, 20Funk D Aebi S Howell SB The role of DNA mismatch repair in drug resistance.Clin Cancer Res. 1998; 4: 1-6PubMed Google Scholar, 21Schmitt CA Lowe SW Apoptosis and therapy.J Pathol. 1999; 187: 127-137Crossref PubMed Scopus (269) Google Scholar The cause of the methylation in these tumours remains elusive. Knowledge of other molecular subtypes may improve understanding of the range of behaviour of these and other important cancers. Diagnosis of such mismatch repair abnormalities used to depend on molecular analysis for microsatellite instability but now rapid antibody methods are available.19Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut (in press).Google Scholar Different mechanisms of causation of cancer may require different approaches to treatment.22Lowe SW Ruley HE Jacks T Housman DE p53-dependent apoptosis modulates the cytotoxicity of anticancer agents.Cell. 1993; 74: 957-967Summary Full Text PDF PubMed Scopus (2951) Google Scholar, 23Lowe SW Bodis S McClatchey A et al.p53 status and the eficacy of cancer therapy in vivo.Science. 1994; 266: 807-810Crossref PubMed Scopus (1540) Google Scholar Histopathologists will need to respond to such challenges.Panel 2Genetic profiles of sporadic colorectal cancersTabled 1Non-mismatch repairMismatch repairAPC mutations and loss of 5qPossible repeat expansions in APCBcl-2 overexpressionTGF-β type-11 receptorKi-ras mutationIGF-IIRp53 mutation, overexpressionBaxor 17p lossMSH3/MSH618q loss DCC/DPC4 mutationPTENMyc amplificationβ2-microglobulinDNA aneuploidDiploidTGF-Transforming growth factor, IGF-Insulin like groeth factor. Open table in a new tab Aetiology of cancerMany cancers have a strong genetic influence but most arise through the interaction of chemical carcinogens and the DNA of stem cells. We already know the link between carcinogens and specific molecular defects24Bennett WP Hussain SP Vahakangas KH Khan MA Sheidls PG Harris CC Molecular epidemiology of human cancer risk; gene-involvement interactions and p53 mutation spectrum in human lung cancer.J Pathol. 1999; 187: 8-18Crossref PubMed Scopus (163) Google Scholar such as aflatoxin and p53 mutations at codon 249, benzpyrene and p53 mutations at codons 157, 248, and 273, and ultraviolet-light injury and CC to TT thymidine-dimer formation. We face not only the prospect of diagnosing an individual's cancer but identifying the specific cause. However, knowing the cause is only the first step to prevention. Although the relation between squamous-cell carcinoma of the lung and smoking has been known for nearly 50 years, it still remains a challenge to reduce smoking in the population—even with overwhelming scientific evidence. Molecular epidemiology has been limited over the past 10 years by the obstacle that extensive DNA-sequencing studies represent. With the advances from the human genome project of large automated workstations for PCR, DNA-sequencing reactions, and higher throughputs on DNA sequencers, mutation analysis of populations will become much easier and expand our knowledge of this important area.Many tumours arise because of either a weak or a strong genetic predisposition. We know some strong genetic predispositions to specific cancers and the molecular defect caused by inactivation of both copies of tumour-suppressor genes such as retinoblastoma (Rb), familial adenomatous polyposis (APG), neurofibromatosis (NF-I, NF-2), and Li Fraumeni (p53). This knowledge has become more important to histopathologists with the discovery of genes involved in commoner cancers such as BRCAI and BRCA225Duncan JA Reeves JR Cooke TG BRCA1 and BRCA2 proteins: roles in health and disease.Mol Pathol. 1998; 51: 237-247Crossref PubMed Scopus (46) Google Scholar in breast cancer, and h-MSH-2, h-MLH-1 h-PMS-1, h-PMS-2, h-MSH626Thorson AG Knezetic JA Lynch HT A century of progress in hereditary nonpolypposis colorectal cancer (Lynch syndrome).Dis Colon Rectum. 1999; 42: 1-9Crossref PubMed Scopus (33) Google Scholar, 27Whitehouse A Meredith DM Markham AF DNA mismatch repair genes and their association with colorectal cancer.Int J Mol Med. 1998; 1: 469-474PubMed Google Scholar, the gene for the typic II receptor of transforming growth factor β,28Lu SL Kawabata M Imamura T et al.HNPCC associated with germline mutation in the TGF-beta type II receptor gene.Nat Genet. 1998; 19: 17-18Crossref PubMed Scopus (140) Google Scholar and polymorphisms in the APC gene29Laken SJ Petersen GM Gruber SB et al.Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.Nat Genet. 1997; 17: 79-83Crossref PubMed Scopus (524) Google Scholar in colorectal cancer.We are often asked whether a patient with a family history has a genetic predisposition. Our ability to confirm a germ-line defect is currently limited but will be less so in the future. Simple tests may be developed that indicate which protein is abnormal and suggest methods for the rapid prediction of a certain gene in a patient—eg, the use of mismatch-repair antibodies to show loss of expression of the same mismatch-repair protein in tumours from multiple members of the family.In the future, we will be faced with the identification of new genes or polymorphisms of known genes which have a smaller effect on the development of cancer. We may be asked to provide a diagnosis for such patients from tissue samples. We already know of one polymorphism that can disrupt APC function and predispose to colorectal cancer in Ashkenazi Jews.29Laken SJ Petersen GM Gruber SB et al.Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.Nat Genet. 1997; 17: 79-83Crossref PubMed Scopus (524) Google Scholar Polymorphisms will also be important in determining an individual's risk of cancer after exposure to a carcinogen such as N-acetyl transferase glutathione S-transferase,30Perera FP Environment and cancer: who are susceptible?.Science. 1997; 278: 1068-1073Crossref PubMed Scopus (544) Google Scholar or response to therapy, or the possible toxicity of a particular treatment. The development of a single-nucleotide polymorphism map will identify the variable bases in the human genome that cause the above differences between individuals. Some 3 X102Jackson DP Hayden JD Quirke P The extraction of nucleic acid from archival material.in: McPherson MJ Quirke P Taylor GR PCR: a practical approach. IRL Press, Oxford1991: 29-50Google Scholar of these will be available in the next 2 years, with half of these positioned on the genome.31Marshall E Drug firms to create public database of genetic mutations.Science. 1999; 284: 406-407Crossref PubMed Scopus (79) Google ScholarStaging of tumoursWill the new biology help with the staging of tumours? Despite the promises of the molecular discoveries of the 1980s and 1990s, the staging of common cancers is still by dissection and histology. Molecular staging is a possibility since individual molecular lesions develop at different times in the progression of a tumour; however they do not always develop synchronously with standard histopathological staging and must be shown to yield more valuable clinical information. Individual lesions may provide little information but molecular profiles may be developed that offer additional value or superior information and will probably occur when we fully understand the processes of invasion and metastasis. Currently, we have only a patchy knowledge of their mechanisms.One area in which molecular techniques appear superior to standard methods is the prediction of minimum residual disease or early relapse by the identification of recurrent clonal populations in bone marrow or peripheral blood.32Negrin RS Minimal residual disease.Curr Opin Hematol. 1998; 5: 488-493Crossref PubMed Scopus (4) Google Scholar There have also been suggestions that molecular analysis can predict spread of disease past the surgical margin in head and neck cancer33Brennan JA Mao L Hruban RH et al.Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck.N Engl J Med. 1995; 332: 429-435Crossref PubMed Scopus (664) Google Scholar and that molecular lesions in peritoneal washings can identify patients with a high risk of relapse in gastric cancer.34Kodera Y Nakanishi H Yamamura Y et al.Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology.Int J Cancer. 1998; 79: 429-433Crossref PubMed Scopus (120) Google Scholar In the future, we may routinely take samples for molecular analysis not only from the surgical specimen and its margins but also, for molecular analysis, from other sites such as peripheral blood, or pelvic or peritoneal washings. However, a note of caution needs to be added. The presence of DNA alone in the peripheral blood or other bodily fluids will not always equate with the presence of cells capable of establishing viable metastases and mutations in oncogenes such as Kirsten ras are not always confined to malignant tumours and can be found in normal mucosa, metaplastic polyps of the colon, and adenocarcinomas,11Minamoto T Yamashita N Ochiai A et al.Mutant K-ras in apparently normal mucosa of colorectal cancer patients: its potential as a biomarker of colorectal tumorigenesis.Cancer. 1995; 75: 1520-1526Crossref PubMed Scopus (64) Google Scholar, 12Nucci MR Robinson CR Longo P Campbell P Hamilton SR Phenotypic and genotypic characteristics of aberrant crypt foci in human colorectal mucosa.Hum Pathol. 1997; 28: 1396-1407Summary Full Text PDF PubMed Scopus (120) Google Scholar Experimental evidence also suggests that DNA can leach from tumours into regional lymph nodes and it may even get to the peripheral blood and give rise to false-positive molecular results.35Yamamoto N Kato Y Yanagisawa A Ohta H Takahashi T Kitagawa T Predictive value of genetic diagnosis for cancer micrometastasis: histologic and experimental appraisal.Cancer. 1997; 80: 1393-1398Crossref PubMed Scopus (1) Google Scholar Careful large clinical studies in a range of tumour types with different targets are required to identify the true value of these assays.Prediction of type of therapy and responseThe histological assessment of oestrogen receptors by immunocytochemistry was rapidly taken up by histopathologists and we are now faced with identifying breast cancers with high amounts of amplification of c-erbB2 for antibody therapy.36Brenner TL Adams VR First MAb approved for treatment of metastatic breast cancer.J Am Pharmaceut Assoc. 1999; 39: 236-238Google Scholar, 37Ross JS Fletcher JA The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy.Stem Cells. 1998; 16: 413-428Crossref PubMed Scopus (609) Google Scholar The new biology may bring other ways of predicting response to various chemotherapy regimens. This is particularly important as we move to more toxic and expensive treatments. A range of markers such as P glycoprotein38Ferry DR Testing the role of P-glycoprotein expression in clinical trials: applying pharmacological principles and best methods for detection together with good clinical trials methodology.Int J Clin Pharmacol Ther. 1998; 36: 29-40PubMed Google Scholar has been claimed to predict response, but carefully conducted randomised studies on large numbers of patients are lacking. These markers need to have been compared with the current gold standard of high-quality histopathology and then reproduced elsewhere with different series of patients. Antibodies to the proteins of key genes in the repair of DNA damage and the apoptosis pathways (ie, mismatch-repair genes, p53, Bcl-2) as well as to key enzymes such as thymidylate synthase for fluorouracil, or topoisomerase 1 for irinotecan, need to be evaluated. Early studies of tumour-suppressor genes in patients treated for colorectal cancer suggest that deletions of 18q and of p53 induce resistance to chemotherapy.39Barratt P, Seymour MT, Stenning S, Birbeck KF, Quirke P, and the AXIS collaborators. Molecular markers to predict survival and benefit from adjuvant intraportal 5FU in colon cancer. 1999 Annual Meeting of the American Society of Clinical Oncology, Atlanta, USA (abstr 1030).Google Scholar Cells in these patients may not be able to recognise DNA damage from chemotherapy due to failure of the apoptotic pathways. In the future, we may assess all tumours this way, with the molecular pathologist suggesting the type of therapy. If we do get good molecular treatments with gene-replacement therapy, we may need to identify the genetic lesions and susceptibilities of a tumour so that specific treatments can be undertaken. We may also be required to monitor the success of therapy by molecular techniques looking for the uptake of the therapeutic nucleic acid or by immunocytochemistry looking for products of reporter molecules in tumour biopsy samples.InfectionHistopathology deals with tissues from many cases of infectious disease. We currently have valuable techniques for the detection of infectious agents in paraffin-embedded tissue. We can amplify DNA for bacterial, viral, or non-culturable infectious agents40Muller C Petermann D Stain C et al.Whipple's disease: comparison of histology with diagnosis based on polymerase chain reaction in four consecutive cases.Gut. 1997; 40: 425-427Crossref PubMed Scopus (40) Google Scholar from paraffin-embedded tissue2Jackson DP Hayden JD Quirke P The extraction of nucleic acid from archival material.in: McPherson MJ Quirke P Taylor GR PCR: a practical approach. IRL Press, Oxford1991: 29-50Google Scholar Viral RNA can be reliably detected by the adoption of suitable methods such as glycogen carriage.41Foy CA Quirke P Lewis FA Futers TS Bodansky HJ A search for candidate viruses in type 1 diabetic pancreas using the polymerase chain reaction.Diabet Med. 1994; 11: 564-569Crossref PubMed Scopus (18) Google Scholar We can, therefore, frequently identify and type an infectious agent definitively when the morphological changes suggest it. Currently this may take several hours, but newer thermal cyclers that use thin-film heaters to heat small volumes of solutions combined with TaqMan fluorescent dyes can shorten this to amplification and detection in 7 min and allow the use of quantitative PCR in the "field"42Belgrader P Benett W Hadley D et al.PCR detection of bacteria in seven minutes.Science. 1999; 284: 449-450Crossref PubMed Scopus (326) Google Scholar This type of procedure is most valuable in acute infectious epidemics, or with agents such as tuberculosis in which current diagnosis by culture is extremely slow. These methods also allow us to identify non-culturable organisms such as Whipple's bacillus40Muller C Petermann D Stain C et al.Whipple's disease: comparison of histology with diagnosis based on polymerase chain reaction in four consecutive cases.Gut. 1997; 40: 425-427Crossref PubMed Scopus (40) Google Scholar and expand our knowledge of its role in disease.The new biology will not only identify currently unknown organisms but also allow us to obtain vast amounts of important information about the infectious organism and the host reaction to it. There are at least 11 bacterial genomes completely sequenced and 50 more projects underway. The complete genome of the tubercle bacillus is now known and such data should yield unprecedented information about the infective agent—eg, antibiotic sensitivity, risk of becoming dormant, ability to become muhidrug resistant, and the source of infection. Information will also be provided by molecular assays of the host. Their predisposition and resistance to the organism may be accurately determined by their genotype, immune profile, and pattern of genetic response to the infection. For example, studies have suggested that patients who are heterozygotes for AF508 are less susceptible to cholera,43Rodman DM Zamudio S The cystic fibrosis heterozygote—advantage in surviving cholera?.Med Hypoth. 1991; 36: 253-258Summary Full Text PDF PubMed Scopus (41) Google Scholar people with certain HLA types such as B27 may be more susceptible to intracellular infectious agents,44Ikeda M Yu DT The pathogenesis of HLA-B27 arthritis: role of HLA-B27 in bacterial defense.Am J Med Sci. 1998; 316: 257-263Crossref PubMed Scopus (19) Google Scholar HIV progression is affected by HLA type,45Roger M Influence of host genes on HIV-1 disease progression.FASEB J. 1998; 12: 625-632PubMed Google Scholar and polymorphisms in interleukins or other cytokines may affect the efficiency of the immune response.46Hurme M Lahdenpohja N Santtila S Gene polymorphisms of interleukin 1 and 10 in infectious and autoimmune diseases.Ann Med. 1998; 30: 469-473Crossref PubMed Scopus (123) Google ScholarGeneticsThis will be dealt with elsewhere and will only be touched on briefly. Archival material can be used for genetic diagnosis and is frequently called on to check the genetic status of deceased relatives of index cases. Suspicious histological findings can be directly confirmed or excluded by molecular testing. For example, in cases of meconium ileus, the cystic-fibrosis mutation status can be established. New methods that simultaneously analyse multiple genes will allow genetic screening of histopathological material from a range of tissues, some of which are currently only cursorily invesfigated—eg, the diagnosis of the presence or absence of fetal parts in early miscarriages may be replaced by diagnostic tests that reveal the cause of the problem. Currently such techniques are confined to gross chromosomal lesions such as trisomies, but in the future it may be possible to do whole genome screens with expression arrays on such material to identify preventable causes of miscarriage.The ability to investigate an individual's genetic predisposition to Huntington's disease, dementia, cardiovascular risk, or others, from any stored surgical or diagnostic material also opens up ethical problems for the histopathologist. We are custodians of an individual's genetic medical record. What rights do
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