NEET PG Medical 2014

1.

An 11-year-old male is diagnosed with leukemia 5 years after having an osteosarcoma removed from his femur and undergoing chemotherapy. His mother died from breast cancer and five other family members in his mother’s family had different cancers. Which of the following genes is the most likely candidate for the cancer in this family?

• APC
• BRCA1
• DCC
• RB1
• TP53

This patient has Li-Fraumeni syndrome, suggested by multiple types of cancers in the same family. The patient has had two different cancers. The mutation occurs in the p53 protein, which is activated by DNA damage or hypoxia to up-regulate expression of proteins participating in apoptosis. If p53 is mutated, this up-regulation cannot occur effectively, and the cell continues to divide, leading to expansion and possibly to malignancy. APC gene expression is involved in familial adenomatous polyposis. BRCA1 expression is associated with breast and ovarian cancers. The RB1 protein is also involved in the cell cycle. It binds to the E2F transcription factor to inhibit transcription, and therefore a mutation will decrease the inhibition. These cancers generally present as retinoblastomas but can also occur in other cells that receive either two spontaneous mutations or a single spontaneous mutation along with one inherited mutation (two-hit hypothesis). DCC is the “deleted in colon cancer” gene and is one of the genes mutated in the progression model of cells going from normal to abnormal to malignant.

2.

A 67-year-old female with a 1-month history of upper abdominal discomfort and weight loss (8 lb) was evaluated for a gastric ulcer. Upper gastrointestinal endoscopy revealed an area of inflammation and biopsy was negative. Computed tomography revealed a 2 × 3-cm gastric mass and a 2-cm lesion on the liver. A biopsy of the hepatic lesion was KIT-positive by immunohistochemistry and a diagnosis of gastrointestinal stromal tumor (GIST) was confirmed. Mutation of the KIT proto-oncogene resulting in tumor formation has most likely affected which molecular mechanism?

• Amplification
• Apoptosis
• Cell cycle checkpoint regulation
• Cell growth pathway
• DNA repair pathway

Students may not be familiar with the KIT mechanism of action. However, there are several clues that lead to the answer. KIT is one of the proto-oncogenes, which are typically gain-of-function mutations associated with cancers, whereas the counterpart to proto-oncogenes is tumor suppressor genes, which are typically loss-of-function mutations. Tumor suppressor proteins keep a tumor from developing by either allowing time in the cycle for repair to occur or by directing the cell to the apoptotic pathway. They are divided into cell division–controlling genes, DNA repair genes, and apoptosis genes. Options B, C, and E are therefore in the tumor suppressor, loss-of-function mutation family. KIT is a receptor tyrosine kinase, or a growth factor receptor gene, and as such if mutated leads to increased cell growth. The gene in this family that students should be best acquainted with is RET, which causes four different diseases depending on the mutation and its localization; mutations will cause both gain of function and loss of function depending upon the type and effect of the mutation. KIT is specific for GIST tumors. Option A refers to triplet repeat amplification that occurs with neurologic disorders.

3.

A 26-year-old male presents with anemia and occult blood in the stool. Flexible sigmoidoscopy reveals several polyps that are removed surgically. Family history reveals several members of the patient’s extended family developed colorectal cancer (CRC) between the ages of 25 and 70 years. The patient is concerned about the cause of colon cancer in his family. Which of the following is the most likely cause of inherited colon cancer in this family?

• Familial adenomatous polyposis
• Hereditary nonpolyposis colon cancer (HNPCC)
• Lynch II syndrome
• Peutz-Jeghers syndrome
• Unknown causes

Attention is often directed toward genetic causes of diseases and the genes involved. In these cases, FAP and HNPCC are the hallmark examples resulting from mutations in APC and mismatch repair genes. This patient has several polyps, as opposed to hundreds of polyps suggesting HNPCC. There is insufficient family history to make a better assessment about the patient, and the vast majority of CRC cases result from mutations in susceptibility genes predisposing the patient to cancer; most of these either are uncharacterized or the mechanisms of any associations between mutations and cancer are preliminary and not well understood. HNPCC is sometimes divided into Lynch I and Lynch II syndromes. The former is associated with right-sided cancer; the latter has a greater association with ovarian and endometrial cancer, among others. Peutz-Jeghers syndrome is associated with benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa.

4.

A routine ophthalmologic examination in a 20-year-old woman demonstrates several well-defined, oval, darkly pigmented lesions, one surrounded by a pale halo, on the retina. Identified as congenital hypertrophy of the retinal pigment epithelium (CHRPE), this condition is most often associated with mutations in which gene?

• APC
• BRCA1
• BRCA2
• FAP
• MLH1

CHRPE is a benign marker associated with colon cancer caused by mutations in the APC gene. FAP, or familial adenomatous polyposis, is the name of the disease caused by these mutations and not a gene itself. BRCA1 and BRCA2 genes are associated with breast and ovarian cancers.MLHI is one of the genes associated with mismatch repair defects and hereditary nonpolyposis colon cancer.

5.

A clinic diagnosed seven new cases of retinoblastoma during a 3-year period. Four cases were inherited and three were sporadic. Which of the following best distinguishes these cases?

• Both inherited and sporadic cases have tumors in both eyes.
• Both inherited and sporadic cases occur in the absence of any affected relatives.
• Inherited cases have tumors in both eyes, whereas sporadic cases have tumors in one eye.
• Two alleles are abnormal at the retinoblastoma locus in inherited retinoblastoma, but only one allele is abnormal in sporadic retinoblastoma.
• Two alleles are normal at the retinoblastoma locus in inherited retinoblastoma, but only one allele is normal in sporadic retinoblastoma.

Retinoblastoma is the model disease for explaining the two-hit hypothesis and tumor suppressor gene mutations. It normally causes confusion for students because tumor suppressor mutations are “inherited in an autosomal dominant manner but expressed in an autosomal recessive manner.” Most individuals who inherit one mutated allele develop a mutation in the normal allele and express the disease; those who do not express the disease demonstrate incomplete penetrance. For those individuals inheriting two normal alleles, it is much less likely that two mutations will occur in the RB alleles. When the latter occurs, it is usually in adults; cancers may often demonstrate mutated RB alleles as a consequence of rapid proliferation and decreased effective time for repair. In this case, children are developing Rb, suggesting they inherited a mutated allele. Inherited cases tend to have tumors in both eyes because all cells inherited the same mutated allele. Sporadic cases tend to have cancers in only one eye because it would require four independent events in the same alleles in two places to develop tumors. Since all cases are children, the leading question is what might be causing an increase in sporadic Rb at this age.