What evidence indicates that mutations in human DNA mismatch repair genes are related to certain forms of cancer?

Genetic tests that detect mutations in the BRCA1 and BRCA2 tumor-suppressor genes are widely available. These tests reveal a number of mutations in these genes—mutations that have been linked to familial breast cancer. Assume that a young woman in a suspected breast cancer family takes the BRCA1 and BRCA2 genetic tests and receives negative results. That is, she does not test positive for the mutant alleles of BRCA1 or BRCA2. Can she consider herself free of risk for breast cancer?

Mutations in tumor-suppressor genes are associated with many types of cancers. In addition, epigenetic changes (such as DNA methylation) of tumor-suppressor genes are also associated with tumorigenesis [Otani et al. (2013).

Expert Rev Mol Diagn 13:445-455].

How might hypermethylation of the TP53 gene promoter influence tumorigenesis?

Mutations in tumor-suppressor genes are associated with many types of cancers. In addition, epigenetic changes (such as DNA methylation) of tumor-suppressor genes are also associated with tumorigenesis [Otani et al. (2013). Expert Rev Mol Diagn 13:445 455].

Knowing that tumors release free DNA into certain surrounding body fluids through necrosis and apoptosis, Kloten et al. [(2013). Breast Cancer Res. 15(1):R4] outlines an experimental protocol for using human blood as a biomarker for cancer and as a method for monitoring the progression of cancer in an individual.

A study by Bose and colleagues (1998). Blood 92:3362-3367] and a previous study by Biernaux and others (1996). Bone Marrow Transplant 17:(Suppl. 3) S45–S47] showed that BCR-ABL fusion gene transcripts can be detected in 25 to 30 percent of healthy adults who do not develop chronic myelogenous leukemia (CML). Explain how these individuals can carry a fusion gene that is transcriptionally active and yet does not develop CML.

Those who inherit a mutant allele of the RB1 tumor-suppressor gene are at risk for developing a bone cancer called osteosarcoma. You suspect that in these cases, osteosarcoma requires a mutation in the second RB1 allele, and you have cultured some osteosarcoma cells and obtained a cDNA clone of a normal human RB1 gene. A colleague sends you a research paper revealing that a strain of cancer-prone mice develops malignant tumors when injected with osteosarcoma cells, and you obtain these mice. Using these three resources, what experiments would you perform to determine:

(a) Whether osteosarcoma cells carry two RB1 mutations

(b) Whether osteosarcoma cells produce any pRB protein

(c) If the addition of a normal RB1 gene will change the cancer-causing potential of osteosarcoma cells?

The table in this problem summarizes some of the data that have been collected on mutations in the BRCA1 tumor-suppressor gene in families with a high incidence of both early-onset breast cancer and ovarian cancer.

Although the mutations listed in the table are clearly deleterious and cause breast cancer in women at very young ages, each of the kindred groups had at least one woman who carried the mutation but lived until age 80 without developing cancer. Name at least two different mechanisms (or variables) that could underlie variation in the expression of a mutant phenotype, and propose an explanation for the incomplete penetrance of this mutation. How do these mechanisms or variables relate to this explanation?

The table in this problem summarizes some of the data that have been collected on mutations in the BRCA1 tumor-suppressor gene in families with a high incidence of both early-onset breast cancer and ovarian cancer.

Examine the types of mutations that are listed in the table, and determine if the BRCA1 gene is likely to be a tumor-suppressor gene or an oncogene.

The table in this problem summarizes some of the data that have been collected on mutations in the BRCA1 tumor-suppressor gene in families with a high incidence of both early-onset breast cancer and ovarian cancer.

Note the coding effect of the mutation found in kindred group 2082. This results from a single base-pair substitution. Draw the normal double-stranded DNA sequence for this codon (with the 5' and 3' ends labeled), and show the sequence of events that generated this mutation, assuming that it resulted from an uncorrected mismatch event during DNA replication.