a. Homozygous for the normal Gardner allele, some smaller mRNA molecules

b. Heterozygous for normal and mutant Gardner allele, some larger mRNA molecules

c. Heterozygous for normal and mutant Gardner allele, some smaller mRNA molecules

d. Homozygous for mutant Gardner allele, no change in mRNA molecules

e. Homozygous for mutant Gardner allele, some larger mRNA molecules

483. A parent is correcting his child’s photograph for red eye and notes that one of the child’s pupils reflects the flash as white rather than red. An ophthalmologist confirms the presence of a tumor in the back of the white-reflecting eye, telling the parents about the possibility of retinoblastoma (MIM* 180200). The parents return to their pediatrician, confused about the relation of retinoblastoma (Rb) and B-cell lymphoma (bcl) genes they saw on the Internet and the possibility that their child’s tumor is inherited. Which of the following is the most appropriate response?

a. Rb and bcl proteins are polymerases that prevent oncogenesis by stringent DNA repair; the parents are therefore carriers for autosomal recessive Rb deficiency with a one in four recurrence risk.

b. Rb protein binds transcription factors needed for cell division and bcl protein (cyclin D1) stimulates it; Rb is a tumor suppressor gene requiring homozygous mutations (two hits) that are likely sporadic in a child with unilateral tumor.

c. Rb and bcl proteins are DNA-binding factors that suppress promoters near oncogenes and act as tumor suppressors; the child represents a new, dominant-acting mutation and the parents have a minimal recurrence risk.

d. Rb protein stimulates cyclins specific for retinal tissue and bcl does the same for lymphatic cyclins; the child represents a new mutation with excess Rb activity.

e. Rb protein forms complexes with bcl protein that promotes cell division in rapidly proliferating tissues; the child represents a new mutation with excess Rb-bcl complex activity.

484. A large family has many individuals with colon cancer, affecting males and females in a manner compatible with autosomal dominant inheritance. The patients do not have multiple polyps as in Gardner syndrome or adenomatosis polyposis coli (APC-MIM*175100), so that colonoscopy screening has not been helpful. The family is thought most compatible with hereditary nonpolyposis colon cancer (HNPCC-MIM*114500), and the diagnosis is confirmed by skin biopsy and fibroblast studies. Which of the following best describes the diagnostic results?

a. Defect in mismatch repair with accumulation of nucleotide repeats by replication slippage

b. Defect in double-strand break repair with accumulation of multiple small DNA fragments

c. Defect in base-excision repair with accumulation of depurinated DNA

d. Defect in nucleotide excision repair with accumulation of thymine dimers

e. Defect in nucleotide excision repair with defects in an MSH protein that is homologous to an E coli mut gene

485. A 25-year-old adopted female uses a private detective to locate her birth hospital and likely biologic mother. She cannot see a family resemblance in this female and becomes concerned because this female had breast cancer at age 31 with several relatives having early-onset breast cancer. Upon questioning, the female recalls that she and her roommate in the hospital were both unwed, delivering on the same day and both giving up their babies for adoption. Which of the following would be the best option for the adopted female to pursue?

a. Compare blood leucocyte DNA for variable patterns of restriction fragments arising from tandemly repeated sequences (microsatellites) between the adoptee and her possible mother.

b. Compare fragment sizes of DNA copied from blood leucocytes using reverse transcriptase between the adoptee and her possible mother.

c. Compare blood leucocyte DNA fragment size distribution as analyzed by gel electrophoresis between the adoptee and her possible mother.

d. Compare HLA gene fragments obtained from blood leucocyte DNA between the adoptee and her mother.

e. Analyze blood leucocyte DNA for breast-ovarian cancer gene mutations (MIM*113705) in the adoptee and her prospective mother.

486. A research study examines the nature of telomeres using DNA probes specific for the 6-nucleotide 5′-TTAGGG-3′ repeats present in variable numbers at chromosome ends. The study includes children and adults with normal and abnormal development, including several patients with cancer (many genetic disorders cause both developmental disability and higher risks for cancer). Which of the following would be a likely result of this study?

a. Longer telomeres in older or disabled patients and in cancer tissues.

b. Shorter telomeres in younger patients and in cancer tissues, longer telomeres in some patients with developmental disabilities.

c. Shorter telomeres in older or disabled patients and in cancer tissues.

d. Longer telomeres in cancer tissue and single, specific telomere rearrangements in some patients with developmental disabilities.

e. Shorter telomeres in cancer tissue and single, specific telomere rearrangements in some patients’ developmental disabilities.

487. A 22-year-old single Ashkenazi Jewish female has a strong family history of breast cancer, with her mother, maternal aunt, and grandmother all having breast cancer before menopause. She understands that the family likely exhibits autosomal dominant inheritance for predisposition to breast cancer due to mutations in the BRCA tumor suppressor genes; a pathologic BRCA mutation causes an ∼80% lifetime risk for breast and 45% risk for ovarian cancer. Her mother undergoes testing and a mutation in the BRCA1 gene (MIM*113705) is found, potentially defining her daughter’s cancer risks. Which of the following maternal test results and consequent lifetime cancer risks for the daughter are most accurate?

a. Homozygous mutation in the BRCA1 TATA box, 80% cancer risk for the daughter

b. Heterozygous mutation in the BRCA1 TATA box, 80% cancer risk for the daughter

c. Heterozygous mutation in the BRCA1 coding sequence changing the third nucleotide in a codon for glycine, 80% cancer risk in the daughter

d. Heterozygous frameshift mutation in the BRCA1 coding sequence, 40% cancer risk for the daughter

e. Homozygous frameshift mutation in the BRCA1 coding sequence, 80% cancer risk for the daughter

488. Cancers may be caused by mutations in two types of genes, those that affect cell proliferation (oncogenes, tumor suppressor genes) and those that control rates of mutation (caretaker genes—ie, those altering DNA repair). A child develops a wide gait and is found to have different leg lengths. On examination, one leg is larger (hemihypertrophy) and a mass is found in the lower abdomen. Surgery reveals a Wilms tumor (MIM*194070), and the IGF2 (insulin-like growth factor 2) gene is known to be specifically overexpressed in Wilms tumor. Restriction analysis of the child’s tumor DNA showed that both IGF2 alleles were undermethylated. It is known that normal adult tissues have one methylated and one undermethylated IGF2 allele, while the single IGF2 allele in sperm DNA is always undermethylated. The results are best summarized as which of the following?

a. A loss of imprinting (LOI) mutation that increased tumor IGF2 expression and identifies IGF2 as a caretaker gene

b. A loss of imprinting (LOI) mutation that increased tumor IGF2 expression and identifies IGF2 as an oncogene

c. A loss of imprinting (LOI) mutation that increased tumor IGF2 expression and identifies it as a tumor suppressor gene

d. A loss of imprinting (LOI) mutation that increased tumor IGF2 expression and causes Wilms tumor in females only

e. A loss of imprinting (LOI) mutation that increased tumor IGF2 expression and causes Wilms tumor in males only

489. An abdominal mass is palpated during a well visit for a 15-month-old African American boy with a normal past medical history. Urinalysis demonstrates blood cells and other cells of unusual morphology, suggesting a diagnosis of Wilms tumor (MIM*194070). The physicians suspected erosion of surrounding kidney with invasion of the renal pelvis, causing tumor cells to be excreted in urine. Because a version of the p57 gene is known to be silenced preferentially in Wilms tumor, analysis of p57 gene methylation and expression was performed on the urine tumor cells with the results shown below (normal cells-N, tumor cells-T). Which of the following best summarizes these results?

a. Bi-allelic p57 gene methylation and with normal p57 gene expression making a diagnosis of Wilms tumor unlikely

b. Bi-allelic p57 gene methylation and with increased p57 gene expression making a diagnosis of Wilms tumor unlikely

c. Bi-allelic p57 gene methylation and with decreased p57 gene expression supporting the diagnosis of Wilms tumor

d. Undermethylation of both p57 alleles with increased p57 gene expression supporting the diagnosis of Wilms tumor

e. Methylation of one p57 allele with increased p57 gene expression supporting the diagnosis of Wilms tumor

490. A 50-year-old Caucasian male presents with a markedly enlarged tonsil and recurrent infections with serum immunoglobulin deficiency. He has enlarged lymph nodes along his neck. Chromosome analysis demonstrates a translocation between the immunoglobulin heavy-chain locus on chromosome 14 and an unidentified gene on chromosome 8. Which of the following is the most likely cause of his phenotype?

a. The translocation has deleted constant chain exons on chromosome 14 and prevented heavy-chain class switching.

b. The translocation has deleted the interval containing diversity (D) and joining (J) regions.

c. The translocation has activated a tumor-promoting gene on chromosome 8.

d. The translocation has deleted the heavy-chain constant chain Cμ so that virgin B-cells cannot produce IgM on their membranes.

e. The translocation has deleted an immunoglobulin transcription factor gene on chromosome 8.

491. The Warburg effect refers to the seemingly paradoxical preference for glycolysis over oxidative phosphorylation in many cancer tissues. Which of the following statements best reflects this paradox?

a. Glycolysis consumes 4 ATP early in the pathway, produces 2 ATP later, and the net of -2 ATP per glucose is less than the 2 ATP produced per oxidation of citrate.

b. Glycolysis consumes 2 ATP early in the pathway, produces 4 ATP later, and the net of 2 ATP per glucose is less than 1/6 of that produced by oxidative phosphorylation.

c. Glycolysis consumes 4 ATP early in the pathway, produces 6 ATP later, and the net of 2 ATP per glucose is less than 1/6 of that produced by oxidative phosphorylation.

d. Glycolysis consumes 2 ATP early in the pathway, produces 4 ATP later, and the net of 2 ATP per glucose is less than the 3 produced by oxidative phosphorylation.

e. Glycolysis consumes 6 ATP early in the pathway, produces 12 ATP later, and the net of 6 ATP per glucose is less than the 8 produced by oxidative phosphorylation.

492. A 45-year-old Caucasian female seeks evaluation for vague complaints of “tired blood” and “rheumatism.” Her physician first considers chronic fatigue syndrome or depression, but performs a complete blood count (CBC) showing a hemoglobin of 9.0 g/dL (normal mean 14), white blood cell count of 3000/mm³ (normal mean 7.4), and platelet count of 30,000/mm³ (normal 150-350). A diagnosis of aplastic anemia is made and bone marrow chromosome studies initiated with knowledge that aplastic anemia can be a preleukemic state. A previously unreported chromosome translocation is found that suggests the female has a very unusual leukemia. The hematology-oncology consultant has no protocols gleaned from experience with like patients to rely on, but wishes to try a metabolic treatment that will inhibit leukemic cell division without using harsh chemotherapy poisons that could further damage the bone marrow. Which of the following strategies would cause the greatest inhibition of DNA synthesis?

a. Lowering aspartate

b. Lowering carbamoyl phosphate

c. Increasing uric acid

d. Increasing glutamine

e. Increasing orotic acid

493. One of the first chemotherapeutic agents was methotrexate, a compound that was effective in killing rapidly dividing cells like those of leukemias. This compound would be expected to elevate concentrations of which of the following compounds?

a. Homocysteine and dUMP

b. Thymine and choline

c. Serine and methionine

d. Glycine and methionine

e. Homocysteine and thymine

494. A 35-year-old Caucasian female notes a lump in her breast and undergoes biopsy that shows breast cancer. The biopsy tissue is sectioned and shown to react with an antibody to the epidermal growth factor (EGF) receptor-2, also called Her-2. Which of the following describes the most likely treatment strategy for this female?

a. Intravenous infusion of EGF to activate signal transduction in normal breast tissue

b. Intravenous infusion of EGF antibody to block signal transduction in breast cancer tissue

c. Oral dosing of EGF to activate signal transduction in normal and breast cancer tissue

d. Oral dosing of EGFR2 antibody (Herceptin) to block signal transduction in normal breast tissue

e. Intravenous infusion of EGFR2 antibody (Herceptin) to block signal transduction in breast cancer tissue

495. Gardner syndrome or adenomatous polyposis of the colon (MIM*175100) is an autosomal dominant condition characterized by retinal changes, extra teeth, skin cysts, and multiple colonic polyps with high rates of malignant transformation. A family is encountered in which a great-grandfather, grandmother, and father are affected with Gardner syndrome and develop intestinal cancer in their thirties. The father brags that none of his four children have inherited Gardner syndrome because they lack skin cysts and have not had cancer. The chance that at least one child has inherited the Gardner syndrome allele and the reason the children have not manifested cancer are which of the following?

a. ¼, ascertainment bias

b. ½, variable cancer predisposition

c. ¾, early-onset disease manifestation

d. ¹/16, incomplete medical evaluation

e. ¹⁵/16, later-onset disease manifestation

496. Studies of the eye tumor retinoblastoma have revealed an Rb locus on the long arm of chromosome 13 that influences retinoblastoma occurrence. Patients with retinoblastoma 13q-deletions often develop bilateral tumors (both sides), in contrast to more common forms of retinoblastoma that occur at one site. Which of the following phrases best explains this phenomenon?

a. Rb is an oncogene.

b. Rb is a tumor suppressor gene.

c. Rb mutations ablate a promoter sequence.

d. Rb mutations ablate an enhancer sequence.

e. Rb mutations must always involve chromosome abnormalities.

497. In Burkitt lymphoma, there is increased expression of a hybrid protein with an amino-terminus similar to immunoglobulin (Ig) heavy chain and an unknown carboxy-terminus. Which of the following best explains this phenomenon?

a. Chromosome translocation that brings together an Ig heavy chain with an oncogene

b. Chromosome duplication involving a segment with an oncogene

c. Chromosome translocation involving a segment with Ig heavy chains

d. Chromosome deletion removing an oncogene

e. Chromosome deletion removing a tumor suppressor gene

498. A couple request genetic counseling because the wife has contracted early-onset breast cancer at age 23. The husband has a benign family history, but the wife has several relatives who developed cancers at relatively early ages. Affected relatives include a sister (colon cancer, age 42), a brother (colon cancer, age 46), mother (breast cancer, age 56), maternal aunt (leukemia, age 45), maternal uncle (muscle sarcoma, age 49), and a nephew through the brother with colon cancer (leukemia, age 8). Which of the following is an accurate conclusion from the family history?

a. No genetic predisposition to cancer, since most individuals have different types of cancer

b. Possible autosomal dominant inheritance or multifactorial inheritance of cancer predisposition

c. Germ-line mutations in an oncogene, with somatic mutations that suppress the oncogene

d. Germ-line mutations in a tumor suppressor gene, with neoplasia from chemical exposure

e. Mitochondrial inheritance of tumor predisposition evidenced by the affected maternal relatives

499. A normal 6-year-old girl has a strong family history of cancer, including several relatives with Li-Fraumeni syndrome, an autosomal dominant condition that predisposes to breast and colon cancer. Her parents request that she have genetic testing for a possible cancer gene. Which of the following is the major ethical concern about such testing?

a. Nonmaleficence

b. Beneficence

c. Autonomy

d. Informed consent

e. Confidentiality

500. Deletions of 11p13 may result in Wilm tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome). In some patients, however, not all features are seen. Additionally, individual features of this syndrome may be inherited separately in a Mendelian fashion. Limited features may also be seen in patients without visible chromosomal deletions. Which of the following is the most likely mechanism for this finding?

a. Mitochondrial inheritance

b. Imprinting

c. Germ-line mosaicism

d. Uniparental disomy

e. Contiguous gene syndrome

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