(This is the second part of a series that began with a previous post – “The Important Role of Rearrangements, Duplications, and Deletions of BRCA1 and BRCA2“.)
In Part 1 of this series, we provided an introduction to the role that large rearrangements of the BRCA1 and BRCA2 genes play in Hereditary Breast and Ovarian Cancer risk.
A newly published research paper has provided a wealth of information about the relative frequency and impact that large rearrangements have on Hereditary Breast and Ovarian Cancer risk in a relatively genetically diverse population from the United States.
We think this is a great opportunity to do two things:
- Discuss some of the key findings from the new study and place them in context.
- Spread the word to BRCA Negative women and families who: (1) may not have had a comprehensive look for BRCA1/BRCA2 mutations at the time they were tested because either sequencing only or sequencing plus the 5-site large rearrangement panel only was done AND (2) may still be looking for explanations for a significant family history of breast and/or ovarian cancer.
Although standard clinical sequencing of BRCA1 and BRCA2 (as implimented in Myriad Genetics’ BRACAnalysis test) does a good job of detecting single base changes and small insertion and deletion mutations (which are like spelling mistakes in the DNA code), it does not do a good job of detecting large rearrangements, deletions, and duplications (which are like additions or subtraction of one or more key paragraphs in the DNA code). As these large rearrangements can confer the same remarkably elevated lifetime risks of breast and ovarian cancer that the smaller deleterious mutations can, alternative tests such as the “BART” test must be added to standard BRCA1 and BRCA2 sequencing in order to have a good comprehensive look for these larger rearrangements.
Some Key Features of Myriad Genetics’ Experience with Large Rearrangement Testing of BRCA1 and BRCA2
In the new paper, Thaddeus Judkins, Dr. Benjamin Roa, and their colleagues describe their experience with identification of large rearrangements in individuals tested at Myriad Genetics for BRCA1 and BRCA2 mutations between July 2007 and April 2011.
They report results for two distinct groups of patients which they refer to as “high-risk” and “elective”.
The high-risk group had the following characteristics:
- Ordered test was “Comprehensive BRACAnalysis”
- Met a set of clinical criteria suggesting that it was relatively likely that they had a BRCA1 or BRCA2 mutation
- 25,535 individuals were in this group
In contrast, the elective group had these characteristics:
- They did not meet the clinical criteria suggesting a relatively high likelihood of a BRCA1 or BRCA2 mutation
- Myriad Genetics’ BART test was ordered as an elective test to be run if there were no deleterious mutation detected by the combination of BRCA1/BRCA2 sequencing and the 5-site Large Rearrangement Panel (more details about the individual tests may be found in the previous post in this series)
- Individuals were excluded if the BART test was cancelled (for a reason other than a positive result from sequencing or the large rearrangement panel – of note, this might include patients for whom payers refused preauthorization of payments for BART, etc.)
- 22,921 individuals were in this group
How Frequent Were Large Rearrangements of BRCA1 and BRCA2?
Overall, in the high-risk group, about 23.8% of patients (~6,077 out of 25,535 tested) were found to have a BRCA1 or BRCA2 mutation of any type.
- 21.5% of the high-risk patients tested had a mutation detected via BRCA1/BRCA2 sequencing
- 2.4% of the high-risk patients had a large rearrangement mutation detected with either the 5-site Large Rearrangement Panel or “BART” testing
- Thus, in this group large rearrangements were just under 10% of the total number of mutations detected
- For the high-risk group, about two-thirds of the identified mutations (including all types of mutations) were in BRCA1 and one-third in BRCA2
The “elective” group, had a lower mutation positive rate: about 8.2% of patients (~1,880 out of 22,921 tested).
- 7.8% of the elective patients had a mutation detected via BRCA1/BRCA2 sequencing
- 0.5% of the elective patients had a large rearrangement mutation detected
- Therefore, in this group, large rearrangements were about 6% of the total number of mutations detected
- For the elective group, about 45% of mutations overall were in BRCA1 and 55% were in BRCA2
A Diversity of Large Rearrangements Were Seen in This Study
Not surprisingly, given the large number of patients tested (48,456), many distinct large rearrangements were seen in the study:
- 81 distinct large rearrangements in BRCA1
- 27 distinct large rearrangements in BRCA2
Three types of large rearrangements were seen:
- 84 deletions
- 23 duplications
- 1 triplication
The greater number of rearrangements in BRCA1 is consistent with the frequent occurence of a genomic structure called “Alu repeats” in and around the gene. Areas of our genomes with these structures tend to be more susceptible to deletions, duplications and other rearrangements.
Additionally, the total number of distinct rearrangements is certainly even greater than these numbers, since the BART test will classify, for example, distinct duplications involving exons 13-15 of BRCA1 with distinct breakpoints in separate patients as the same duplication seen twice. Thus, although the BART test is very useful for identifying large rearrangements conferring Hereditary Breast and Ovarian Cancer risk, higher resolution techniques would be necessary for many of the rearrangements seen recurrently in this study in order to know whether it is truly the same rearrangement seen recurrently (versus distinct rearrangements that happen to involve generally the same area of the gene).
Next Time: Large Rearrangements in Patients of Latin American and Caribbean Ancestry
It’s clear from both this report and from other data in the literature that certain large rearrangements can play a big role in patients with particular ancestry. Large rearrangements play a particularly important role in patients of Latin American and/or Caribbean ancestry and we’ll cover this in the next post in this series.
Part 3 of this series on the important role that BRCA1/BRCA2 large rearrangements play – “Large Rearrangements Equal Big Impact in Hereditary Breast and Ovarian Cancer Patients of Latin American and Caribbean Ancestry” will be available at CancerAndYourGenes on Wednesday, June 6, 2012.
Stay Tuned for the Other Posts in this Series on Mondays
Part 3 – “Large Rearrangements Equal Big Impact in Hereditary Breast and Ovarian Cancer Patients of Latin American and Caribbean Ancestry” (Wednesday – June 6, 2012)
Part 4 – “Large Rearrangements in Hereditary Breast and Ovarian Cancer Patients with African Ancestry” (Friday – June 8, 2012)
Part 5 – “What Patients Need to Know About BRCA1 and BRCA2 Large Rearrangement Testing” (Monday – June 11, 2012)
Part 6 – “Large Rearrangements in BRCA1 and BRCA2 – What Physicians and Genetic Counselors Need to Know” (Monday – June 18, 2012)
Part 7 – “Towards a Future in Which Testing for All BRCA1 and BRCA2 Mutations is Both Integrated and Routine” (Monday – June 25, 2012)
Do You Have a BRCA1 or BRCA2 Mutation?
If you have a BRCA1 or BRCA2 mutation, you may find our website BRCAscoop.com to be an extremely useful source of independent, non-industry-influenced, high-quality Hereditary Breast and Ovarian Cancer information and education.
Are You BRCA Negative and Wondering Whether There May be Another Gene Behind Your Family History of Breast and/or Ovarian Cancer?
Check out The BRCA Negative Book project for answers and an opportunity to get involved!
Judkins T, Rosenthal E, Arnell C et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 2012 (published online ahead of print Apr 27 2012)
Myriad and BRACAnalysis are trademarks of Myriad Genetics, Inc., registered in the U.S. and other countries. Myriad Genetics, Inc. funded the work by Judkins et al. published in Cancer which we are independently discussing.