The Case: While Elizabeth is reading the morning newspaper, she notices an ad fo
ID: 162352 • Letter: T
Question
The Case: While Elizabeth is reading the morning newspaper, she notices an ad for a free genetic screening for breast cancer at the clinic next week.The ad specifically invites women of Ashkenazi Jewish ancestry to participate.According to the newspaper ad, subjects will be tested to see whether they have mutations in the BRCA1 gene which would predispose them to breast cancer. Elizabeth, age 27, had heard about the discovery of the gene and about the mutation linked to Jewish women. Her paternal grandmother had been diagnosed with breast cancer at age 51 and died two years later, and Elizabeth worried that she may have inherited a variant that would put her at increased risk. She also worried about her mother, age 52 and apparently cancer-free so far, and her 7- year old daughter. Her daughter is not allowed to participate in the screening, but Elizabeth convinces her mother to go with her to get tested. For the screening, a small amount of blood is drawn. DNA is isolated from the blood, and part of the BRCA1 gene is amplified by PCR. Using a Southern Blot method, the digested DNA is run on a gel, transferred to a neutral membrane. Once on the membrane, the samples are hybridized with specific probes corresponding to deleterous mutations known to be linked to increased breast cancer susceptibility, plus probes for wild type regions of BRCA1. The probe will only bind to the DNA if that mutation is present. Control DNA samples, known to have a specific mutation, are included in the run to verify probe . Probe binding is visualized by labels attached to the probe, and will depend on the lab running the analysis. Probes: 185delAG (AG deletion in exon 2) Normal 185 (no mutation at this site) 4184delTCAA (TCAA deletion in exon 11) Normal 4184 5382insC (C insertion in exon 13) Normal 5382 DNA samples: Elizabeth Mother Unrelated woman Control 185delAG Control 4184delTCAA Control 5382insC Control wild type BRCA1 (no mutations) If either Elizabeth or her mother test positive, is a prophylactic double mastectomy appropriate? (2 marks) What other issues does this type of testing raise, and how should these issues be addressed? (2 marks) What does it mean if a result came back as a Variant of Uncertain Clinical Significance? Provide a peer-reviewed journal article as a reference for this question. (1 mark answer, 1 mark reference) Does the lack of any of these mutations mean that the women will not get breast cancer? (2 marks) Who should have access to the test results? (2 marks) Does the daughter have the right to know the results? She is only seven now, but what about when she is 16? (3 marks) Should this type of screening be mandatory? (3 marks)
Explanation / Answer
ANS:
The DNA sequence files are from the human BRCA1 gene, GenBank accession number U14680, locus HSU14680, 5711 bp. Mutated sequence files were created by introducing the indicated nucleotide deletions or insertions into the text file prior to filtering. The probes are approximately 20 bp sequences spanning the mutation region and containing the mutated sequences. The wild type probe is from a BRCA1 region outside any of the mutated regions so it is unchanged in all sequence file.
1) Elizabeth - positive for 185delAG mutation
Mother - positive for 185delAG mutation
Unrelated Woman - positive for 5382insC mutation
2) Elizabeth - no mutations detected
Mother - positive for 185delAG mutation
Unrelated Woman - positive for 4184delTCAA mutation
3)Elizabeth - positive for 185delAG mutation
Mother - no mutations detected
Unrelated Woman - positive for 5382insC mutation
4) Elizabeth - positve for 4184delTCAA mutation
Mother - positive for 4184delTCAA mutation
Unrelated Woman - positive for 185delAG mutation
Issues: If either Elizabeth or her mother test positive, is a prophylactic double mastectomy appropriate? Does the lack of any of these mutations mean that the women will not get breast cancer? Who should have access to these test results? Does the daughter have the right to know the results? She is only seven now, but what about when she is 16? Should this type of screening be mandatory?