p.1
Genetic Lesions in Solid Tumors
What are the three main types of genetic lesions that cause solid-tissue tumors?
Deletion or inactivation of tumor suppressor genes, mutation in or overexpression of oncogenes, and hypermethylation of the promoter regions.
p.1
Genetic Lesions in Solid Tumors
What is the impact of oncogenic mutations downstream of EGFR on cancer treatment?
Mutations in downstream targets like ras-p21 and BRAF can reduce the effectiveness of anti-EGFR agents.
p.1
Techniques in Cancer Molecular Pathology
What is the preferred tissue source for molecular pathology in solid tumors and why?
Fresh tissue is preferred because it best preserves DNA, RNA, or protein, although paraffin-embedded tissue is more commonly used due to availability and ease of access.
p.1
Techniques in Cancer Molecular Pathology
What are some common techniques used in cancer molecular pathology?
Common techniques include PCR, RT-PCR, branched DNA testing, FISH, CGH, and next-generation sequencing (NGS).
p.6
Genetic Lesions in Solid Tumors
What are the four molecular subtypes of breast cancer based on gene expression profiling?
Luminal-like, normal-like, Her2-positive, and basal-like.
p.3
Genetic Lesions in Solid Tumors
What are the major molecular targets in bladder cancer?
Aneuploidy of chromosomes 3, 7, and 17 and/or deletion of the 9p21 (encoding p16); NMP22.
p.5
Genetic Lesions in Solid Tumors
What is the most common mutation in IDH1?
A heterozygous point mutation with substitution of arginine by histidine at residue 132 (R132H).
p.2
Specific Solid Tumor Pathologies
What is indicated by the combined loss of 1p and 19q in oligodendrogliomas?
The combined loss of 1p and 19q is typical in oligodendrogliomas and is associated with better prognosis and response to chemotherapy.
p.5
Techniques in Cancer Molecular Pathology
What ratio is considered abnormal in Her2/neu FISH assays for breast cancer?
Her2/neu:CEP17 signal ratio ≥ 2.0.
p.5
Genetic Lesions in Solid Tumors
What is the typical genetic alteration in primary glioblastoma involving EGFR?
EGFR amplification, found in 36% of primary GBMs.
p.3
Genetic Lesions in Solid Tumors
What are the major molecular targets in glioblastoma?
EGFR, TP53, 10q, MGMT, mutations in TP53 and PTEN, P16INK4a deletions.
p.3
Genetic Lesions in Solid Tumors
What molecular target is associated with gastric cancer of the intestinal type?
p73 mutations, MSI (MLH1 and MSH2), LOH/mutations of APC genes, Her2/neu.
p.1
Molecular Diagnostics in Solid Tumors
How has the application of molecular genetics to solid tumors impacted diagnostic pathology?
It has revolutionized diagnostic pathology by providing accurate diagnosis, classification, prognosis, and treatment of solid tumors.
p.1
Clinical Applications of Molecular Pathology
How has molecular diagnosis expanded beyond its original use in solid tumors?
It is now an indispensable tool for predicting clinical outcomes, including disease prognosis, selection of optimal therapeutic regimens, and response to treatment.
p.5
Prognostic and Predictive Biomarkers
What is the significance of IDH1 mutation in gliomas?
It is a strong, independent positive prognostic biomarker in diffuse gliomas, glioblastomas, and oligodendrogliomas.
p.2
Personalized Medicine and Cancer Treatment
What are some treatment options for glioblastoma multiforme (GBM) based on molecular genetics?
Treatment options include tyrosine kinase inhibitors like erlotinib and gefitinib, especially for primary tumors with EGFR upregulation.
p.1
Next-Generation Sequencing in Oncology
Why is next-generation sequencing (NGS) significant in cancer treatment?
NGS is widely used for pathway-based therapy selection and predicting treatment resistance in many types of cancer.
p.2
Genetic Lesions in Solid Tumors
What types of genetic alterations are involved in carcinogenesis of solid tumors?
Genetic alterations can be inherited or result from carcinogenesis and include polygenic mutations, unique specific genetic alterations, and epigenetic components.
p.5
Genetic Lesions in Solid Tumors
How common are IDH2 gene mutations compared to IDH1 mutations?
Much less common, affecting 3% to 5% of cases.
p.5
Genetic Lesions in Solid Tumors
What genetic abnormality is commonly seen in atypical teratoid/rhabdoid tumors (AT/RT)?
Loss of all or part of chromosome 22, particularly involving 22q11.2.
p.2
Prognostic and Predictive Biomarkers
Why is the 1p/19q status important in the prognosis and treatment response of oligodendrogliomas?
The 1p/19q status is associated with better prognosis, slower growth, and better response to chemotherapy.
p.3
Techniques in Cancer Molecular Pathology
Which methods are mainly used to detect genetic alterations in glioblastoma?
RT-PCR, methylation-specific PCR, FISH.
p.3
Genetic Lesions in Solid Tumors
Which genetic alterations are commonly found in sporadic, nonhereditary breast cancer?
Her2/neu, multiplex genes.
p.6
Techniques in Cancer Molecular Pathology
What are some concerns associated with IHC-based assays for multiple markers?
Concerns include the nonlinear nature of IHC staining, different subcellular localizations of markers, and the impact of different slide-scoring thresholds.
p.7
Molecular Diagnostics in Solid Tumors
What is the purpose of the OncotypeDx assay in breast cancer?
To detect breast cancers with a low potential for recurrence.
p.6
Clinical Applications of Molecular Pathology
What is the function of the monoclonal antibody CB11 produced by Ventana Medical Systems?
CB11 is used for Her2/neu response indication and is FDA-approved for use in combination with FISH.
p.6
Next-Generation Sequencing in Oncology
What is the Prosigna Breast Cancer Assay and what does it measure?
It is based on the PAM50 gene expression signature and measures the expression levels of 50 genes to classify a tumor into intrinsic subtypes and provide a risk of recurrence score.
p.6
Molecular Diagnostics in Solid Tumors
What is the OncotypeDx assay and what does it determine?
OncotypeDx is a 21-gene multiplex RT-PCR assay that determines the 10-year risk for disease recurrence in patients with ER-positive, lymph node-negative tumors.
p.5
Molecular Diagnostics in Solid Tumors
What is the clinical significance of INI1 deletions in AT/RT?
Detected in the majority of AT/RT cases and used as a diagnostic marker.
p.7
Prognostic and Predictive Biomarkers
For which patient population is the MammaPrint assay intended?
For lymph node-negative breast cancer in women younger than 61 years of age with an ER-positive or ER-negative tumor.
p.6
Genetic Basis of Cancer
What technologies have expanded the knowledge of genomic pathways in breast cancer?
Whole-genome profiling technologies.
p.1
Genetic Lesions in Solid Tumors
What is a common genetic mutation found in several types of cancer and what therapy does it enable?
Overexpression of the epidermal growth factor receptor (EGFR), which allows for the implementation of anti-EGFR therapy.
p.7
Prognostic and Predictive Biomarkers
Which pathways are most influential in RS calculation for breast cancer?
The proliferation and ER pathways are the most influential, followed by the Her2 pathway.
p.6
Prognostic and Predictive Biomarkers
What are the prognostic factors measured by IHC in breast cancer?
ER, PR, Her2/neu, and the proliferation marker Ki-67.
p.2
Molecular Diagnostics in Solid Tumors
What types of specimens are used for molecular pathology to assist in the diagnosis of superficial solid tumors?
Cytologic specimens, including cells from fine-needle aspiration (FNA), urine, blood, and swabs.
p.2
Specific Solid Tumor Pathologies
What are the major molecular targets of glioblastomas?
The major molecular targets are EGFR, TP53, 10q LOH, and deletion of the MGMT gene.
p.2
Specific Solid Tumor Pathologies
How does the molecular genetics differ between primary and secondary glioblastomas?
Primary glioblastomas show activation of the EGFR pathway, while secondary glioblastomas are more commonly associated with TP53 mutations.
p.5
Specific Solid Tumor Pathologies
What type of tumors are rhabdoid tumors?
Highly malignant (WHO grade IV) embryonal CNS tumors of infants and very young children.
p.1
Techniques in Cancer Molecular Pathology
Why might paraffin-embedded tissue result in false-negative results in molecular pathology?
Because exposure to formalin can cause nucleic acid fragmentation and reduce the integrity of DNA, RNA, and protein.
p.1
Familial Cancer Syndromes
Why is molecular genetic pathology important for familial cancer screening?
It allows for the detection of genetic alterations in close relatives of patients with familial cancer, enabling rapid detection and potentially earlier treatment.
p.5
Genetic Basis of Cancer
What is the role of IDH1 and IDH2 enzymes?
The conversion of isocitrate to α-ketoglutarate with the simultaneous reduction of NADP+ to NADPH.
p.2
Specific Solid Tumor Pathologies
How is the loss of heterozygosity (LOH) on chromosome 10 significant in glioblastoma multiforme (GBM)?
LOH on chromosome 10 is the most frequent genetic loss in GBM, occurring in 60% to 80% of cases.
p.3
Genetic Lesions in Solid Tumors
Which mutations are prevalent in pancreatic cancer?
KRAS mutations, TP53, SMAD4, p16/CDKN2A inactivation.
p.6
Personalized Medicine and Cancer Treatment
Which breast cancer subtypes are associated with the highest rates of pathologic complete response to neoadjuvant multiagent chemotherapy?
Basal-like and Her2-positive subtypes.
p.6
Prognostic and Predictive Biomarkers
What clinical utility has been demonstrated by the Prosigna Breast Cancer Assay in clinical trials?
It provides prognostic information of distant recurrence in hormone receptor–positive, postmenopausal breast cancer patients treated with endocrine therapy.
p.5
Specific Solid Tumor Pathologies
In which types of gliomas is IDH1 commonly mutated?
Astrocytic, oligodendroglial, and oligoastrocytic gliomas (WHO grades II to III) as well as in secondary glioblastomas (WHO grade IV).
p.5
Techniques in Cancer Molecular Pathology
What methods are primarily used to determine the copy number of the Her2/neu gene in breast cancer?
FISH (Fluorescent In Situ Hybridization).
p.3
Genetic Lesions in Solid Tumors
What genetic alterations are frequently seen in hepatocellular carcinoma (liver cancer)?
EGFR, PIK3CA, p53, β-catenin, microRNA (miR-122a), multiple genes.
p.3
Genetic Lesions in Solid Tumors
What are common genetic alterations in prostate cancer?
TMPRSS2 to transcripts of the ETS family member genes: overexpression of ETS proteins (e.g., ERG, ETV1, ETV4, ETV5).
p.7
Prognostic and Predictive Biomarkers
What mRNA levels are associated with a low RS in breast cancer?
High relative levels of ER mRNA and low levels of Ki-67 proliferation gene mRNA.
p.2
Molecular Diagnostics in Solid Tumors
Which molecular tests are used for breast cancer, cervical cancer, and bladder cancer diagnoses?
Her-2/neu for breast cancer, HPV testing for cervical cancer, and UroVysion for bladder cancer.
p.2
Genetic Lesions in Solid Tumors
What are some examples of tumor suppressor genes (TSGs) involved in solid tumors?
Rb, SMAD, adenomatous polyposis coli (APC).
p.3
Genetic Lesions in Solid Tumors
Which genetic alterations are associated with papillary thyroid cancer?
BRAF, RAS, RET, PTC1, PTC3.
p.2
Genetic Lesions in Solid Tumors
What role do oncogenes play in solid tumors and can you name some examples?
Oncogenes promote cancer development. Examples include EWS, cKIT, Her2/neu, KRAS, and BRAF.
p.3
Genetic Lesions in Solid Tumors
What genetic alterations are associated with high-grade serous ovarian cancer?
p53 deletion/mutation, Wnt/β-catenin or PI3K/PTEN signaling pathway defects.
p.7
Prognostic and Predictive Biomarkers
What does a tripartite RS (Recurrence Score) of 17, 18-30, and >30 indicate in breast cancer risk?
RS 17 indicates low risk, RS 18-30 indicates intermediate risk, and RS >30 indicates high risk.
p.7
Prognostic and Predictive Biomarkers
What significant impact did the MammaPrint assay have according to the RASTER trial?
It could spare 32% of patients from chemotherapy for whom it would have been recommended by a standard decision tool.
p.4
Genetic Lesions in Solid Tumors
Which major molecular targets are associated with melanoma?
CDKN2A, p14, p16 inactivation; NRAS (G12V) and BRAF (V600E) oncogenic mutations.
p.4
Genetic Lesions in Solid Tumors
Which specific gene translocation is involved in Ewing’s sarcoma?
t(11;22)(q24;q12) translocation; fusion of EWSR1 and an ETS family gene, mainly FLI1.
p.7
Prognostic and Predictive Biomarkers
How does the MammaPrint assay format its results as opposed to the OncotypeDx test?
The MammaPrint test uses a dichotomous “high risk versus low risk” result format.
p.7
Techniques in Cancer Molecular Pathology
Why is RNA extraction through tissue macrodissection or microdissection recommended?
It is highly enriched for invasive carcinoma and not diluted with benign tissues and in situ carcinoma areas.
p.7
Prognostic and Predictive Biomarkers
Which single gene is shared between OncotypeDx and MammaPrint assays?
The SCUBE2 gene, which is a member of the ER pathway.
p.4
Genetic Lesions in Solid Tumors
What chromosomal translocation is found in congenital fibrosarcoma?
t(12;15)(p13;q25) translocation.
p.4
Familial Cancer Syndromes
What major genes are involved in familial adenomatous polyposis syndrome?
APC (long arm of chromosome 5) or MutY human homologue (MYH).
p.7
Familial Cancer Syndromes
What is the cumulative risk for developing breast and ovarian cancer by age 70 in BRCA1 mutation carriers?
50% to 70% for breast cancer and 30% to 40% for ovarian cancer.
p.4
Genetic Lesions in Solid Tumors
Which genes are involved in congenital fibrosarcoma?
Fusion of ETS gene, ETV6 with neurotropin receptor, NTRK3 gene.
p.4
Familial Cancer Syndromes
What gene is associated with von Hippel–Lindau syndrome (VHL)?
VHL tumor suppressor gene (three exons) on chromosome 3p25.
p.4
Genetic Lesions in Solid Tumors
What chromosomal translocation is found in alveolar rhabdomyosarcoma (ARMS)?
t(2;13)(q35:q14) translocation that results in fusion of PAX3 with FOXO1A.
p.7
Techniques in Cancer Molecular Pathology
What is the main advantage of multiplex qRT-PCR over IHC in breast cancer analysis?
The number of genes that can be simultaneously assessed is significantly greater.
p.7
Familial Cancer Syndromes
What percentage of hereditary breast cancer can be attributed to BRCA gene mutations?
Approximately 15% of familial risk for breast cancer.
p.4
Techniques in Cancer Molecular Pathology
What are the methods used to detect Ewing’s sarcoma?
RT-PCR, FISH, Southern blot.
p.4
Techniques in Cancer Molecular Pathology
Which methods are used to detect familial adenomatous polyposis syndrome?
PCR, sequencing, Southern blot.
p.4
Genetic Lesions in Solid Tumors
What pathways are activated in leiomyosarcoma (LMS)?
PI3K-AKT pathway and mTOR.
p.4
Techniques in Cancer Molecular Pathology
Which diagnostic methods are used for congenital fibrosarcoma?
RT-PCR, FISH, Southern blot.
p.4
Techniques in Cancer Molecular Pathology
Which diagnostic methods are used for gastrointestinal stromal tumors (GIST)?
PCR, sequencing, Southern blot.
p.4
Familial Cancer Syndromes
Which gene is associated with MEN type 1?
MEN 1 tumor suppressor gene.
p.4
Genetic Lesions in Solid Tumors
What gene fusion is involved in dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF)?
Fusion of COL1A1 gene on chromosome 17 with PDGFB gene on chromosome 22.
p.4
Familial Cancer Syndromes
What are the characteristics of von Hippel–Lindau syndrome (VHL)?
Characterized by hemangioblastomas in the CNS and retina, pheochromocytomas, renal cysts and clear cell renal cell carcinoma, pancreatic cysts and islet cell tumors, endolymphatic sac tumors, and papillary cystadenomas of the epididymis and broad ligament.
p.4
Genetic Lesions in Solid Tumors
What genes are fused in synovial sarcoma (SS)?
SS18(SYT) gene with one of the SSX genes (SS18-SSX1, SS18-SSX2, or SS18-SSX4).
p.4
Genetic Lesions in Solid Tumors
What are the downstream targets of fusion proteins in synovial sarcoma?
CCND1 (cyclin D1) and TLE1.
p.4
Familial Cancer Syndromes
What gene mutations are associated with MEN type 2?
RET (chromosome 10q11.2) encoding a tyrosine kinase.
p.4
Genetic Lesions in Solid Tumors
What genetic lesions are associated with leiomyosarcoma (LMS)?
Loss of 1p12-pter, 2p, 13q14-q21 (Rb pathway), 10q (PTEN), 16q, and gains of 17p, 8q, and 5p14-pter.
p.4
Familial Cancer Syndromes
What pathway is involved in familial juvenile polyposis syndrome?
TGF-β signal transduction pathway.
p.4
Familial Cancer Syndromes
What protein is encoded by the VHL gene?
VHL protein, which is critical in regulating hypoxia-inducible factor (HIF-α and -β).
p.4
Familial Cancer Syndromes
Which germline mutations are associated with familial juvenile polyposis syndrome?
SMAD4, BMPR1A, and ENG; also mutations in BMPR1A.
p.4
Familial Cancer Syndromes
What is the genetic basis of Lynch syndrome (HNPCC)?
Microsatellite instability (MSI) in mismatch repair (MMR) genes including MLH1, MSH2, MSH6, MLH3, and PMS2.
