BRCA mutation

Combined methods advocated for BRCA mutation testing

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Multiplex ligation-dependent probe amplification (MLPA) should be incorporated into standard BRCA1/BRCA2 mutation testing because full gene sequencing alone may miss large genomic rearrangements (LGRs) that account for more than 6 percent of mutations in individuals at high risk for hereditary breast/ovarian cancer, new data from Hong Kong have shown.

Sanger sequencing and next-generation sequencing (NGS), commonly used in BRCA mutation testing, can identify small point mutations but not LGRs. “This leads to an underestimation of the rate of mutation and, therefore, a risk of giving patients a false-negative genetic report,” wrote researchers from The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital, and Stanford University School of Medicine. [Cancer Genet 2015;208:448-454]

In 1,236 high-risk patients with breast and/or ovarian cancer recruited through the Hong Kong Hereditary Breast Cancer Family Registry between 2007 and 2014, MLPA identified 8 LGRs that were not detected by Sanger sequencing or NGS. These LGRs accounted for 6.67 percent of the 120 deleterious BRCA mutations identified in the study population (8.77 percent [5 of 57] of BRCA1 mutations and 4.76 percent [3 of 63] of BRCA2 mutations).

Patients in the study underwent MLPA together with full gene sequencing for BRCA1 and BRCA2 by Sanger sequencing or NGS. The NGS platform used had a sensitivity at least equal to that of gold-standard Sanger sequencing.

“Validation of sequencing is important for laboratories to ensure good quality mutation testing,” lead investigator Dr. Ava Kwong of the HKU and the Hong Kong Hereditary Breast Cancer Family Registry  told MIMS Oncology. “The relatively high frequency of LGRs identified in BRCA mutation carriers in our study indicates the need for combining MLPA and full gene sequencing to provide more comprehensive information in routine BRCA1 and BRCA2 mutation screening.”

Heritable genetic changes in the open.

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To correctly interpret human genetic variation in hereditary disorders, researchers and clinicians should populate databases that distribute aggregated information on the clinical significance of these variants.

Closely linked to the recent Supreme Court decision (docket 12-398) limiting the scope of patenting human genes, discussion has been growing about whether anonymized data collected by genetic testing laboratories should be freely available. The perceived unwillingness by some companies, who often are the sole provider of a particular test, to share such anonymized data on genetic variants has drawn sharp criticism from researchers and clinicians.

Myriad Genetics provides a good illustration for how big the difference between what is known by a company and what is available to the community can be. Until the court decision, the company held the monopoly on testing for hereditary mutations in the DNA repair proteins BRCA1 and BRCA2; some of these mutations confer a high risk for breast and ovarian cancer. With data from an estimated 1 million tested patients, Myriad’s database allows high-accuracy classification of a patient’s variants as one of four classes indicating the degree of pathogenicity. Only 3% of the variants Myriad encounters in the United States fall into a fifth class, that of variants of unknown significance (VUSs).

In contrast, with freely accessible databases, an average of 15% of BRCA1 and BRCA2 variants cannot be classified and remain VUSs, says Alvaro Monteiro, who is part of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium focused on classifying BRCA mutations.

This puts researchers outside of Myriad, as well as clinicians, at a considerable disadvantage with respect to fully understanding the impact that changes in these genes can have.

Myriad’s and other companies’ hands may be tied when it comes to data sharing. According to a company spokesperson, Myriad is subject to oversight from the Clinical Laboratory Improvement Amendments and the US Food and Drug Administration. “Consistent with these regulations, we are not allowed to distribute our variant databases, as they may only be used to interpret clinical test results for patients tested in our laboratories.” The company does, however, collaborate with researchers, given their appropriate institutional approval, to help classify VUSs in the context of a specific study and allows the results to be published.

This is a laudable, if small, step that may narrow the knowledge gap, but scientists want to bring information on all variants into the public domain on a much larger scale and are organizing efforts to that end. These efforts will stand or fall depending on community support.

Robert Nussbaum from the University of California, San Francisco, started a grassroots effort, the Sharing Clinical Reports Project (SCRP), appealing to patients and clinicians to share data on BRCA testing in appropriately anonymized form. The aggregated data are submitted to open databases such as the Breast Cancer Information Core (BIC) or ClinVar. SCRP is ready to submit its first 1,885 variants, including 351 that are new to BIC, according to Lawrence Brody, who founded BIC in 1995. These numbers show that the project resonates with people and is gaining traction.

ClinVar strives to be the most comprehensive of such databases. Founded in 2012 and hosted by the US National Center for Biotechnology Information, it aims to collect information on variation in any gene that affects human health, together with phenotypic information for such variants. It currently hosts around 38,000 variants (in about 3,000 genes) from about 90 different submitters, including genetic-testing laboratories from industry and academia.

ClinVar does not provide recommendations for medical diagnosis to patients or physicians. It is meant to be a resource for scientists, clinicians and genetic counselors who want to investigate a particular variant and its clinical implications in more detail.

Hopefully community support to expand the number of genes that ClinVar covers will increase. To ensure high data quality, ClinVar will need independent confirmatory submissions on each gene variant. More detailed phenotypic description of the conditions associated with each variant and the likely pathogenicity, where appropriate, would further enhance value.

It is hard to forecast whether genetic testing will increase in the wake of the Supreme Court decision. Lawsuits filed by Myriad Genetics and other plaintiffs against Ambry Genetics and Gene by Gene on 9 and 10 July, respectively, indicate looming legal battles. Regardless, efforts such as SCRP and ClinVar need support to ensure that genetic information is shared in appropriate forms to benefit not only individual patients but the research community at large.

Source: http://www.nature.com

Does Diagnostic Radiation Increase Breast Cancer Risk in Women with BRCA Mutations?

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European questionnaire-based study leaves the question unanswered.

Because ionizing radiation can damage DNA, diagnostic x-ray exposure in individuals with defects in DNA repair mechanisms (such as those associated with BRCA1 and BRCA2 mutations) could lead to excess risk for cancer. Investigators surveyed women with documented BRCA1/2 mutations in the Netherlands, France, and the U.K. to evaluate any association between radiation exposure and later development of breast cancer. Questionnaires were administered to BRCA1/2 carriers from 2006 to 2009 to elicit their recollections of the type and number of diagnostic procedures they had received in their lifetimes. Estimates of radiation doses to the breast during each type of diagnostic procedure (mammography, fluoroscopy, and computed tomography and conventional radiography of the chest or shoulder) were used to determine total cumulative dose. Cases that were diagnosed >5 years before completion of the study questionnaire were excluded to prevent survival bias.

Of the 1993 participants, 43% (mean age, 49.7) had received diagnoses of breast cancer. Self-reported exposure to any form of diagnostic radiation before age 30 was associated with significantly higher risk for breast cancer (hazard ratio, 1.90; 95% confidence interval, 1.20–3.00), and risk rose with increasing cumulative dose. A history of mammography before age 30 was associated with nonsignificantly increased risk for breast cancer (HR, 1.43; 95% CI, 0.85–2.40). No evidence of excess risk was found for diagnostic radiation exposure between ages 30 and 39.

Comment: As with other epidemiologic studies of diagnostic radiation and risk for breast cancer in BRCA1/2 mutation carriers, the results of this study are inconclusive. The retrospective questionnaire design is subject to recall bias, especially given that women were asked to recollect events occurring up to 30 years earlier. Moreover, no attempt was made to document the date and type of radiologic tests that were reported. Furthermore, estimates of cumulative radiation dose were hypothetical and subject to wide variation based on factors in individuals as well as facilities. Until further data are obtained, the National Comprehensive Cancer Network recommendation of screening with magnetic resonance imaging and mammography in BRCA mutation carriers beginning at age 25 should be followed.

Source: Journal Watch Oncology and Hematology

 

 

 

Irradiation Heightens Risk for Breast Cancer in Women with BRCA Mutations .

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Diagnostic radiation studies, especially if done before age 30, increase the risk that women who carry BRCA mutations will develop breast cancer, according to a BMJ study.

Researchers asked some 2000 carriers of BRCA1 or BRCA2 mutations to recall their history of radiation exposure. Based on standard tables, the cumulative radiation dose to the breast was calculated. Compared with no exposure before age 30, the hazard ratios for breast cancer increased with quartiles of increasing cumulative exposure, reaching 3.8 in the highest quartile.

The authors estimate that among 100 BRCA carriers at age 40, roughly 9 will have developed breast cancer. The number would increase by 5 if all had had a mammogram before age 30.

They conclude that their results support using non-ionizing radiation imaging techniques, such as MRI, as the main surveillance tool in young BRCA carriers.

Source: BMJ