Kristopher R. Bosse, Stephen P. Hunger
Cancer is a complex of diseases arising from alterations that can occur in a wide variety of genes. Multiple mutations, some germline but most acquired (somatic), are required for cells to become fully malignant. These mutations lead to alterations in normal cellular processes that control cell proliferation and survival, including signal transduction, cell-cycle control, DNA repair, cellular growth and differentiation, translational regulation, senescence, and apoptosis (programmed cell death).
Two major classes of genes are implicated in the development of cancer: oncogenes and tumor-suppressor genes. Protooncogenes are cellular genes that are important for normal cellular function and code for various proteins, including transcription factors, growth factors, and growth factor receptors. These proteins are vital components in the network of signal transduction that regulate cell growth, division, and differentiation. Protooncogenes can be altered to form oncogenes —genes that, when translated, can result in the malignant transformation of a cell.
Oncogenes can be divided into 5 different classes based on their mechanisms of action. Changes in any of these normal cellular components can result in unchecked cell growth. Some oncogenes code for growth factors that bind to a receptor and stimulate the production of a protein. Other oncogenes code for growth factor receptors , which are proteins on the cell surface. When growth factors bind to a growth factor receptor, they can turn the receptor on or off. Mutational or posttranslational modifications of the receptor can result in a receptor being permanently turned on, with consequent unregulated growth. Signal transducers or effectors make up another class. Signal transducers are responsible for taking the signal from the cell surface receptor to the cell nucleus. Transcription factors are molecules that bind to specific areas of the DNA and control transcription. MYC and MYCN are examples of transcription factors that when activated by mutation or amplification cause overstimulation of cell division. The final class of oncogenes interferes with apoptosis . Cells that no longer respond to the signal to die can lead to uncontrolled cell proliferation.
The 3 main mechanisms by which protooncogenes are activated are amplification , mutation , and translocation or interstitial deletion (Table 519.1 ). MYC or MYCN, which code for proteins that regulate transcription, are examples of protooncogenes that are activated by amplification. Patients with neuroblastoma in which the MYCN gene is amplified 10-300–fold have a worse clinical outcome. Point mutations can also activate protooncogenes. The NOTCH1 protooncogene codes for a membrane-bound receptor integral to cell fate and differentiation pathways during normal development that undergoes proteolytic cleavage on ligand-induced activation, so that the protein can enter the nucleus and activate target gene transcription. NOTCH1 is mutated in at least 50% of T-cell acute lymphoblastic leukemias, resulting in a constitutively activated protein important in leukemogenesis.
Table 519.1
Oncogene Activators of Pediatric Tumors
| MECHANISM | CHROMOSOME | GENES | PROTEIN FUNCTION | TUMOR |
|---|---|---|---|---|
| Chromosomal translocation | t(9;22) | BCR-ABL1 | Chimeric tyrosine kinase | CML, ALL |
| t(1;19) | TCF3 (E2A)-PBX1 | Chimeric transcription factor | ALL | |
| t(8;14) | MYC-IGH | Transcription factor | Burkitt lymphoma | |
| t(15;17) | PML-RARα | Chimeric transcription factor | APML | |
| 11q23 and others (over 50 fusions partners) | KMT2A (MLL) | Regulation of gene expression | Infant leukemia, ALL, AML, treatment-related leukemias | |
| t(12;21) | ETV6-RUNX1 | Chimeric protein | ALL | |
| t(2;13) or t(1;13) | PAX3 or 7-FOXO1 | Transcription factor | Rhabdomyosarcoma | |
| t(11;22) | EWS-FLI1 | Transcription factor | Ewing sarcoma | |
| Gene amplification | 2p | MYCN | Transcription factor | Neuroblastoma |
| 7p | EGFR | Growth factor receptor, tyrosine kinase | Glioblastoma, lung cancer | |
| Point mutation | 1p or 12p | NRAS or KRAS | Guanosine triphosphatase | AML, ALL, JMML, rhabdomyosarcoma, neuroblastoma |
| 10q | RET | Tyrosine kinase | MEN2 | |
| 2p | ALK | Tyrosine kinase | Neuroblastoma | |
| 9q | NOTCH1 | Transmembrane receptor | ALL |
ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; APML, acute promyelocytic leukemia; CML, chronic myelogenous leukemia; JMML, juvenile myelomonocytic leukemia; MEN2, multiple endocrine neoplasia, type 2.
The 3rd mechanism by which protooncogenes become activated is chromosomal translocation or interstitial deletion. In some leukemias and lymphomas, transcription factor–controlling sequences are relocated in front of T-cell receptors or immunoglobulin genes, resulting in dysregulated transcription of these genes and leukemogenesis. A prominent example are translocations that bring c-MYC under control of the immunoglobulin heavy-chain gene (IGH ) or the kappa (IGκ ) or lambda (IGλ ) light-chain genes in Burkitt's lymphoma . Chromosomal translocations that join genes from 2 different chromosomes or interstitial deletions or inversions within a chromosome can also result in fusion genes ; transcription of the fusion gene results in production of a chimeric protein with new and potentially oncogenic activity. Examples of cancers associated with fusion genes include the childhood solid tumors Ewing sarcoma [t(11;22)] and alveolar rhabdomyosarcoma [t(2;13) or t(1;13)] . These translocations result in novel messenger RNA transcripts that are useful as diagnostic markers. The best-described translocation in leukemia is the Philadelphia chromosome t(9;22 ), which produces the BCR-ABL1 protein found in chronic myelogenous leukemia and specific subtypes of acute lymphoblastic leukemia. BCR-ABL1 is a constitutively active tyrosine kinase. In addition, the protein is localized to the cytoplasm instead of the nucleus, exposing the kinase to a new spectrum of substrates.
Alteration in the regulation of tumor-suppressor genes is another mechanism involved in oncogenesis. Tumor-suppressor genes are important regulators of cellular growth and apoptosis. They have been called recessive oncogenes because the inactivation of both alleles of a tumor-suppressor gene is required for expression of a malignant phenotype.
Knudson's “2-hit” model of cancer development was based on the eye tumor retinoblastoma developing at a significantly younger age in children with the familial vs the sporadic form of the disease, and that tumors were often multifocal in familial cases but were almost always unifocal in sporadic cases. Knudson postulated that sporadic cases of retinoblastoma required somatic mutations to inactivate both copies of a gene, whereas in familial cases, children must inherit an inactivated allele from 1 parent and consequently only require the somatic inactivation of the 1 remaining normal allele. This hypothesis was proven correct 15 years later with the discovery of the RB tumor-suppressor gene.
Another major tumor-suppressor protein is TP53 , which is known as the “guardian of the genome” because it detects the presence of chromosomal damage and prevents the cell from dividing until repairs have been made. In the presence of damage beyond repair, TP53 initiates apoptosis and the cell dies. More than 50% of all tumors have abnormal TP53 proteins. Mutations in the TP53 gene are important in many cancers, including breast, colorectal, lung, esophageal, stomach, ovarian, and prostatic carcinomas, as well as gliomas, sarcomas, and some leukemias.
Several syndromes are associated with an increased risk of developing malignancies, which can be characterized by different mechanisms (Table 519.2 ). One mechanism involves the inactivation of tumor-suppressor genes such as RB in familial retinoblastoma . Interestingly, patients with retinoblastoma in which 1 of the alleles is inactivated throughout all the patient's cells are also at a very high risk for developing osteosarcoma. A familial syndrome, Li-Fraumeni syndrome , in which 1 mutant TP53 allele is inherited, also has been described in patients who develop sarcomas, leukemias, adrenocortical carcinoma, and cancers of the breast, bone, lung, and brain. Neurofibromatosis (NF) is a condition characterized by the proliferation of cells of neural crest origin. NF patients are at a higher risk of developing nervous system tumors, breast cancer, leukemia, pheochromocytomas, and other tumors. NF is inherited in an autosomal dominant manner, although 50% of cases present without a family history and occur secondary to the high rate of spontaneous mutation of the NF1 gene.
Table 519.2
Familial or Genetic Susceptibility to Malignancy
| DISORDER | TUMOR/CANCER | COMMENT |
|---|---|---|
| CHROMOSOMAL DELETION/ANEUPLOIDY SYNDROMES | ||
| Chromosome 11p deletion syndrome | Wilms tumor | Also known as WAGR syndrome (Wilms tumor, a niridia, g enitourinary abnormalities, mental r etardation); deletion typically includes WT1 gene |
| Chromosome 13q deletion syndrome | Retinoblastoma, sarcoma | Associated with intellectual disability, characteristic craniofacial abnormalities; deletion typically includes RB1 gene |
| Trisomy 21 | ALL, AML, AMKL, TMD | Risk of ALL is increased 20-fold, risk of AMKL is increased 500-fold; high cure rates; more prone to chemotherapy toxicity; AMKL associated with GATA1 mutations |
| Klinefelter syndrome (47, XXY) | Breast cancer, extragonadal germ cell tumors | |
| Trisomy 8 | Myeloid neoplasms | Most commonly mosaic trisomy 8 |
| Monosomy 5 or 7 | AML, MDS | |
| CHROMOSOMAL INSTABILITY SYNDROMES | ||
| Xeroderma pigmentosum | Basal cell and squamous cell carcinomas, melanoma | Autosomal recessive; failure to repair UV-damaged DNA; XP gene mutations |
| Fanconi anemia | AML, MDS, rare head, neck, and skin tumors, GI and GU cancers | Autosomal recessive; chromosome fragility; positive diepoxybutane (DEB) test result; mutations in FANCX gene family (includes at least 15 members) |
| Bloom syndrome | AML, MDS, ALL, lymphoma, and solid tumors | Associated with growth deficiency, malar rash; autosomal recessive; increase sister chromatid exchange (SCE); mutations in BLM gene; member of the RecQ helicase gene (unwinds DNA) |
| Ataxia-telangiectasia | Lymphoma, leukemia, less often central nervous system and other solid tumors | Associated with progressive ataxia, oculocutaneous telangiectasias; autosomal recessive; sensitive to radiation-induced DNA damage; increased risk of treatment-related morbidity; biallelic mutation in ATM tumor-suppressor gene |
| Nijmegen breakage syndrome | Leukemia, lymphoma | Associated with microcephaly, characteristic facies, immunodeficiency; biallelic mutations in NBN gene |
| Werner syndrome (progeria) | Soft tissue sarcomas, osteosarcoma, melanoma | Associated with accelerated aging; autosomal recessive; mutations in WRN gene |
| IMMUNODEFICIENCY SYNDROMES | ||
| Wiskott-Aldrich syndrome | Lymphoma, leukemia | Associated with thrombocytopenia, eczema, and recurrent infections; X-linked recessive; WASP gene mutations |
| X-linked lymphoproliferative syndrome (XLP) | B-cell lymphoproliferative disease, lymphomas, HLH | Associated with fulminant and often fatal EBV infection; X-linked; mutations in the SH2D1A gene |
| X-linked agammaglobulinemia (XLA) | Lymphoproliferative disorders, colorectal cancer | Associated with absence of B cells; X-linked; mutations in BTK gene |
| Severe combined immunodeficiency (SCID) | Leukemia, lymphoma | X-linked or autosomal recessive; mutations in IL2RG and ADA genes |
| SYNDROMES ARISING FROM GENE MUTATIONS | ||
| Neurofibromatosis 1 | Neurofibroma, optic glioma, acoustic neuroma, astrocytoma, meningioma, pheochromocytoma, rhabdomyosarcoma, MPNST, neuroblastoma, leukemias | Associated with café-au-lait macules, axillary/inguinal freckling, Lisch nodules; autosomal dominant; mutations in tumor-suppressor gene NF1 |
| Neurofibromatosis 2 | Bilateral acoustic neuromas, meningiomas | Autosomal dominant; mutations in tumor-suppressor gene NF2 |
| Tuberous sclerosis | Facial angiofibromas, renal cell carcinoma, renal angiomyolipomas, myocardial rhabdomyoma | Autosomal dominant; mutations in tumor suppressor gene TSC1 or TSC2 |
| Noonan syndrome | JMML, ALL, neuroblastoma, brain tumors | Associated with distinct facial features, short stature, and heart defects; autosomal dominant; caused by RAS/MAPK pathway mutations (most frequently PTPN11 ) |
| Gorlin-Goltz syndrome (nevoid basal cell carcinoma syndrome) | Multiple basal cell carcinomas, medulloblastoma | Associated with odontogenic keratocysts, skeletal and skin anomalies; autosomal dominant; mutations in PTCH1 or SUFU gene |
| Li-Fraumeni syndrome | Osteosarcoma, soft tissue sarcoma, acute leukemias, breast and brain cancer, adrenal cortical tumors | Autosomal dominant; mutations in TP53 tumor-suppressor gene |
| Beckwith-Wiedemann syndrome (BWS) | Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma | Associated with macrosomia, macroglossia, hemihypertrophy, omphalocele; epigenetic/genomic alterations of chromosome 11p15 |
| Von Hippel–Landau syndrome | Hemangioblastomas of the brain and retina, pheochromocytoma, renal cell carcinoma | Autosomal dominant; mutations of tumor-suppressor VHL gene |
| Multiple endocrine neoplasia, type 1 (Wermer syndrome) | Parathyroid, pancreatic islet cell and pituitary tumors | Associated with hyperparathyroidism, ZES; autosomal dominant; mutations in MEN1 tumor suppressor gene |
| Multiple endocrine neoplasia syndrome, type 2A (Sipple syndrome) | Medullary thyroid carcinoma, parathyroid tumors, pheochromocytoma | Associated with hyperparathyroidism; autosomal dominant; mutations in RET gene |
| Multiple endocrine neoplasia type 2B (multiple mucosal neuroma syndrome) | Mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma | Associated with Marfan habitus, neuropathy; autosomal dominant; mutations in RET gene |
| Familial adenomatous polyposis (FAP) | Colorectal, thyroid, stomach and small intestinal cancer, hepatoblastoma | Associated with multiple colon polyps; autosomal dominant; mutations in APC gene |
| Juvenile polyposis syndrome | Colorectal, stomach, small intestinal and rectal cancer | Autosomal dominant; mutations in BMPR1A and SMAD4 gene |
| Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) | Colorectal cancer, endometrial and stomach cancer, many other cancers | Autosomal dominant; mutations in DNA mismatch repair genes MSH2, MLH1, PMS1, PMS2, and MSH6 |
| Turcot syndrome | Colorectal cancer, brain tumors (glioblastoma, medulloblastoma) | Autosomal dominant; mutations in APC or MLH1 gene |
| Gardner syndrome | Colorectal cancer, other tumors similar to FAP | Subtype of FAP; autosomal dominant; mutations in APC gene |
| Peutz-Jeghers syndrome | Breast cancer, colorectal cancer | Associated with hamartomatous polyps of GI tract; freckling of mouth, lips, fingers, and toes; autosomal dominant; mutations in STK11 gene |
| Hereditary hemochromatosis | Hepatocellular carcinoma | Autosomal dominant; mutations in HFE gene; malignancy associated with cirrhotic liver |
| Glycogen storage disease type 1 (von Gierke disease) | Hepatocellular carcinoma, liver adenomas | Autosomal recessive; mutations in G6PC or SLC37A4 gene |
| Diamond-Blackfan anemia (DBA) | Colorectal and other GI cancers, AML, MDS, osteogenic sarcoma | Autosomal dominant; mutations in the small or large subunit-associated ribosomal protein genes (most often RPS19 ) |
| Shwachman-Diamond syndrome | AML, MDS | Associated with neutropenia, diarrhea, and failure to thrive; autosomal recessive; mutations in SBDS gene |
| DICER1 syndrome | Pleuropulmonary blastoma (PPB), cystic nephromas, ovarian-Sertoli-Leydig tumors, multinodular goiter | Autosomal dominant; associated with mutations in DICER1 gene |
| Familial neuroblastoma | Neuroblastoma | Autosomal dominant; mutations in ALK or PHOX2B gene |
| Hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) | Paraganglioma, pheochromocytomas | Autosomal dominant; mutations in the mitochondrial enzyme succinate dehydrogenase protein family (SDHA, B, C, or D ) |
| Severe congenital or cyclic neutropenia | AML, MDS | Associated with increased bacterial infections; typically autosomal dominant; mutations in ELANE or HAX1 (Kostmann syndrome) gene |
ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; AMKL, acute megakaryocytic leukemia; GI, gastrointestinal; GU, genitourinary; HLH, hemophagocytic lymphohistiocytosis; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; MPNST, malignant peripheral nerve sheath tumor; TMD, transient myeloproliferative disorder; ZES, Zollinger-Ellison syndrome.
A 2nd mechanism responsible for an inherited predisposition to develop cancer involves defects in DNA repair. Syndromes associated with an excessive number of broken chromosomes caused by repair defects include Bloom syndrome (short stature, photosensitive telangiectatic erythema), ataxia-telangiectasia (childhood ataxia with progressive neuromotor degeneration, ocular telangiectasias), and Fanconi anemia (short stature, skeletal and renal anomalies, pancytopenia). As a result of the decreased ability to repair chromosomal defects, cells accumulate abnormal DNA that results in significantly increased rates of cancer, especially leukemia. Xeroderma pigmentosum likewise increases the risk of skin cancer because of defects in repair to DNA damaged by ultraviolet light. These disorders display an autosomal recessive pattern.
The 3rd category of inherited cancer predisposition is characterized by defects in immune surveillance. This group includes patients with Wiskott-Aldrich syndrome , severe combined immunodeficiency, common variable immunodeficiency, and the X-linked lymphoproliferative syndrome. The most common types of malignancy in these patients are lymphoma and leukemia. Cure rates for immunodeficient children with cancer are much poorer than for immunocompetent children with similar malignancies, suggesting a role for the immune system in cancer treatment as well as in cancer prevention.
Genome-wide association studies (GWAS) in a diverse array of childhood tumors, including ALL and neuroblastoma, have defined common single nucleotide polymorphisms (SNPs) in genes that are associated with cancer predisposition and collectively define regions of the genome that are critical in tumorigenesis. These alterations may occur in the coding or noncoding regions of the genome and typically lead to a relatively modest increase in cancer risk (2-10–fold over background) compared to the cancer susceptibility syndromes previously discussed, which may be associated with a lifetime risk of 50–100% of developing cancer. Furthermore, whole genome sequencing efforts across diverse pediatric cancers have identified that at least 8% of children who develop malignancy have a germline cancer-predisposing gene mutation. Many of these predisposing mutations occur in children without a family history of cancer or a known cancer predisposition syndrome.
Several viruses have been implicated in the pathogenesis of malignancy. The association of the Epstein-Barr virus (EBV) with Burkitt lymphoma and nasopharyngeal carcinoma was identified more than 40 years ago, although EBV infection alone is not sufficient for malignant transformation. EBV is also associated with mixed cellularity and lymphocyte-depleted Hodgkin disease, as well as some T-cell lymphomas, which is particularly intriguing because EBV normally does not infect T lymphocytes. The most conclusive evidence for a role of EBV in lymphogenesis is the direct causal role of EBV for B-cell lymphoproliferative disease in immunocompromised persons, especially those with HIV infection or those receiving immunosuppression after organ transplantation. Human herpesvirus 8 (HHV-8) is associated with the development of Kaposi sarcoma.
Children who are chronically infected with hepatitis B virus (hepatitis B surface antigen positive) have a 100-fold increased risk of developing hepatocellular carcinoma . In adults the latency period between viral infection and development of hepatocellular carcinoma approaches 20 yr. However, in children who acquire the viral infection through perinatal transmission, the latency period can be as short as 6-7 yr. The additional factors that are required for the malignant transformation of virally infected hepatocytes are not clear. Hepatitis C virus infection is another risk factor for hepatocellular carcinoma and is also associated with a subset of B-cell non-Hodgkin's lymphomas such as splenic lymphoma.
Almost all cervical carcinomas are caused by human papillomaviruses (HPVs) . High-risk HPVs include types 16 and 18 but also types 31, 33, 34, 45, 52, and 58, which together cause >90% of cervical cancers. Vaccines against the major oncogenic subtypes are now available and are likely to save hundreds of millions of lives worldwide. The low-risk HPVs, including 6 and 11, that are commonly found in genital warts, are almost never associated with malignancies. Like other virus-associated cancers, the presence of HPV alone is not sufficient to cause malignant transformation. The mechanism by which the HPV-associated oncoproteins HPV E6 and E7 induce malignant transformation is thought to involve both the TP53 and the RB tumor-suppressor protein, as well as other pathways that are critical in cell cycle progression, maintenance of telomerase and genomic stability, and apoptosis.
The development of cancer has also been linked to genomic imprinting, which is the selective inactivation of 1 of 2 alleles of certain genes depending on parental origin. Beckwith-Wiedemann syndrome (BWS) , the most commonly identified imprinting disorder, is an overgrowth syndrome characterized by macrosomia, macroglossia, hemihypertrophy, omphalocele, and renal anomalies that is also associated with an increased risk of Wilms tumor, hepatoblastoma, rhabdomyosarcoma, neuroblastoma, and adrenocortical carcinoma. This increased risk in developing cancer is directly associated with changes in the promoter methylation patterns (or loss of heterozygosity) of imprinted genes on chromosome 11p15.5. Normally, the maternally derived IGF2 (insulin-like growth factor receptor 2) allele at this genomic locus is inactivated, thus suppressing IGF2 expression. However, children with BWS show a gain of methylation in this promoter region, which allows for expression from both maternal and paternal IGF2 alleles, leading to growth factor overexpression. Concurrently, the neighboring maternal H19 gene (which encodes ncRNA and miRNA critical in growth suppression), is silenced by this hypermethylation, ultimately resulting in a progrowth phenotype and predisposition to tumor development.
Telomeres are a series of tens to thousands of TTAGGG repeats at the ends of chromosomes that are important for stabilizing the chromosomal ends and limiting breakage, translocation, and loss of DNA material. With DNA replication there is a progressive shortening of telomere length, which is a hallmark of cellular aging and acts as replicative senescence signal. In a majority of cancers, telomerase (encoded by the TERT gene), an enzyme that adds telomeres to the ends of chromosomes, becomes activated, usually through mutations in the TERT promoter. The telomerase-driven maintenance of telomere length in tumors enables unrestrained cellular proliferation by relieving a main checkpoint to cellular life span.