(this is the 1st part of a 7 part series)
The Hereditary Breast and Ovarian Cancer risk genes, BRCA1 and BRCA2, are the most important genetic risk factors known for breast and ovarian cancer. Individuals with a disease-associated mutation in one of these genes have markedly elevated breast cancer and ovarian cancer risks. The identification of a BRCA1 or BRCA2 mutation in a family means that relatives have a tool (being tested for the same mutation) that can help clarify whether they have similarly elevated risks of breast/ovarian cancer or, alternatively, risks that are closer to the general population. Individuals with identified mutations can be screened for breast cancer more aggressively (with breast MRI for example) and can consider breast and ovarian cancer risk reduction approaches (risk-reducing bilateral salpingo-oophorectomy for example).
Types of Mutations in BRCA1 and BRCA2
Several types of mutations in the BRCA1 and BRCA2 genes can cause Hereditary Breast and Ovarian Cancer risk. Most are small:
Single Base Changes in the DNA Sequence
This category includes mutations that interfere with the production or function of a normal BRCA1 or BRCA2 protein in one of several different ways.
Small Insertions or Deletions
These mutations also lead to Hereditary Breast and Ovarian Cancer risk because they interfere with the production or function of a normal BRCA1 or BRCA2 protein.
Both single base changes and small insertions or deletions can be identified by routine clinical BRCA1 and BRCA2 testing – which is most often done with a technique called Sanger sequencing. However, there is a distinct category of BRCA1 and BRCA2 mutations – large rearrangements (duplications, deletions, etc.) – which are often not identifiable by routine DNA sequencing (particularly with Sanger sequencing which is most often used in clinical laboratories).
These large rearrangements are significantly bigger than the small insertions or deletions of a few DNA bases discussed above. Instead, they involve the duplication, deletion, or other rearrangement of much bigger pieces of the BRCA1 or BRCA2 genes (entire exons or even the entire genes).
It’s not absolutely necessary for you to understand the science behind why certain mutations are detectable only with certain clinical laboratory techniques. The important point that you need to know is that routine clinical sequencing (with Sanger sequencing methods) does not detect large genomic rearrangements, and that these can cause disease risk in the case of the BRCA1 and BRCA2 genes and Hereditary Breast and Ovarian Cancer (and just about every other genetic condition).
Importance of Large Rearrangements in BRCA1 and BRCA2
In the United States, clinical testing for BRCA1 and BRCA2 mutations has been performed only at Myriad Genetics due to their intellectual property position. Initially, BRCA1 and BRCA2 testing involved sequencing the genes only. Thus, it was useful for detecting deleterious single base changes and small insertions or deletions that could cause Hereditary Breast and Ovarian Cancer risk. However, for technical reasons, which I won’t go into here, Sanger sequencing is unable to detect many large rearrangements, deletions and duplications.
Initially, it was not entirely clear what fraction of BRCA1 and BRCA2 mutations were undetectable via the initial test; however, reports of large genomic rearrangements undetectable by the test began to trickle out. As most BRCA1 and BRCA2 testing was initially performed in individuals and families of European descent, the large rearrangements that were initially described were primarily found in individuals of European descent. A number of reports of the importance of these in families with normal BRCA1 and BRCA2 sequencing results (see reference list below) ultimately led Myriad Genetics to begin offering – as an adjunct to their BRACAnalysis BRCA1 and BRCA2 sequencing test – a test to detect five of the most common large rearrangements seen in BRCA1 in European populations (Myriad calls this test the 5-site Large Rearrangement Panel).
Although this was a useful addition to their testing menu, research groups around the world began to incorporate a wide variety of techniques that could screen for large rearrangements anywhere in the two genes. This led the Hereditary Breast and Ovarian Cancer community to appreciate several things:
1. Although the 5 rearrangements in the Myriad’s Large Rearrangement Panel test were not uncommon in individuals of European descent, when research groups comprehensively screened for large rearrangements in Hereditary Breast and Ovarian Cancer families with normal BRCA1 and BRCA2 sequencing, many more rearrangements involving numerous areas of both genes were found.
2. It became increasingly clear that particular rearrangements were more common in certain racial/ethnic backgrounds.
3. The lack of a clinically available more comprehensive test for large rearrangements in BRCA1 and BRCA2 led to a situation in which large rearrangements in individuals of non-European backgrounds could not be tested for.
Subsequently, Myriad Genetics made available another test, called “BART” (BRACAnalysis Rearrangement Test), which could more comprehensively look for large rearrangements in BRCA1 and BRCA2.
In the U.S., depending on an individual’s personal and family history of cancer, the BART test is automatically performed in conjunction with sequencing for high-risk cases and is sometimes performed (on an elective basis) for lower risk cases if sequencing does not reveal a BRCA1 or BRCA2 mutation.
Myriad Genetics has Published a New Overview of Their Clinical Testing Experience with Large Rearrangements of BRCA1 and BRCA2
Although Myriad Genetics has been testing a very large number of patients for large rearrangements over the last decade, there has been – to date – a limited window into the overall results of this testing. A new paper, published in the journal Cancer, provides an update on their experience with large rearrangement testing for patients tested between July 2007 and April 2011. The paper describes a massive amount of experience with large rearrangement testing, so we’ve decided to devote a series of posts to assessing the implications of this new paper for individuals and families who may be at risk for Hereditary Breast and Ovarian Cancer and the physicians and genetic counselors who care for them.
We’ll post Part 2 soon We’ve posted Part 2 of the series and will have additional posts in this series over the next five weeks.
Stay Tuned for the Other Posts in this Series
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.
Judkins T, Rosenthal E, Arnell C et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 2012 (published online before print Apr 27 2012)
Hendrickson BC, Judkins T, Ward BD et al. Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families. Genes Chromosomes Cancer 2005; 43:309-13.
Hogervorst FB, Nederlof PM, Gille JJ et al. Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method. Cancer Research 2003; 63:1449-53.
Nordling M, Karlsson P, Wahlström J et al. A large deletion disrupts the exon 3 transcription activation domain of the BRCA2 gene in a breast/ovarian cancer family. Cancer Research 1998; 58:1372-5.
Petrij-Bosch A, Peelen T, van Vliet M et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nature Genetics 1997; 17:341-5.
Puget N, Stoppa-Lyonnet D, Sinilnikova OM et al. Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Research 1999; 59:455-61.
Puget N, Torchard D, Serova-Sinilnikova OM et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Research 1997; 57:828-31.
The BRCA1 Exon 13 Duplication Screening Group. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. American Journal of Human Genetics 2000; 67:207-12.
Unger MA, Nathanson KL, Calzone K et al. Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. American Journal of Human Genetics 2000; 67:841-50.
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.