BRCA Cancer Risk Differs With Type and Location of Mutations

Ricki Lewis, PhD

April 07, 2015

Certain types of mutation in specific parts of the BRCA1 and BRCA2 genes can alter the risk for breast or ovarian cancer, according to results from a study published in the April 7 issue of JAMA.

"The study results fit in with the spectrum of precision medicine," first author Timothy R. Rebbeck, PhD, professor of epidemiology at Penn Medicine and associate director for population science at the Abramson Cancer Center in Philadelphia, told Medscape Medical News. "This is a step from 'oh, you have a mutation' to 'what mutation do you have and what risk does it correspond to?' "

"This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations," the researchers write.

However, Dr. Rebbeck explained, these risks should not be used in genetic counseling because they do not account for the effects of other conditions on life expectancy. The next step will be to determine what level of risk change makes a difference in patients' choices regarding preventive measures, he said.

"These data don't change the way that testing is done. We still require full sequencing as the standard protocol. What it does is help us better interpret and use the information," Dr. Rebbeck noted.

Certain Mutations Linked With Earlier Cancer Diagnosis

The analysis extends beyond the three "founder" BRCA mutations initially identified in the Ashkenazi Jewish population.

Because both BRCA1 and BRCA2 are tumor suppressor genes, the most pathogenic mutations are deletions. Particularly deleterious are nonsense mutations that generate premature stop codons when nonsense-mediated decay fails to destroy the partial transcripts, leading to the synthesis of toxic partial proteins. Mis-sense mutations are very rare in these genes.

The researchers used data from the multinational Consortium of Investigators of Modifiers of BRCA (CIMBA) initiative to estimate hazard ratios for the cancers according to mutation type, function, and position in the gene. The primary study outcome was the diagnosis of breast or ovarian cancer. They calculated the ratio of breast to ovarian cancer hazard ratios, in which a value greater than 1 indicates an elevated risk for breast cancer and a value less than 1 indicates an elevated risk for ovarian cancer.

Of the 19,581 women with a BRCA1 mutation, 9052 (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) with no cancer.

Of the 11,900 women with a BRCA2 mutation, 6180 (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) with no cancer.

For breast cancer, the mean age at diagnosis was 39.9 years in the BRCA1 cohort and 42.8 years in the BRCA2 cohort. For ovarian cancer, the mean age at diagnosis was 50.0 years in the BRCA1 cohort and 54.5 years in the BRCA2 cohort.

The analysis of hazard risk ratios revealed breast cancer cluster regions (BCCRs) and ovarian cancer cluster regions (OCCRs). BRCA1 harbors three BCCRs, one of which is in a highly conserved domain (RING) that has been associated with increased risk for breast cancer. The single OCCR lies within exon 11, a highly mutagenic region in the middle of its 24-exon structure. BRCA2 contains three BCCRs and three OCCRs.

"Mutations in extreme regions [the ends] of the BRCA1 gene are more likely to increase susceptibility to breast cancer and mutations in the central portion of the gene, around exon 11, are more likely to increase susceptibility to ovarian cancer," summed up Dr. Rebbeck. The association between risk and gene topography could provide clues to the mechanism of carcinogenesis, he added.

An age effect was slightly significant for both genes. For BRCA1, mutations in exon 11 were associated with earlier age at diagnosis for either cancer, whereas mutations conferring premature stop codons were associated with later age at diagnosis for breast cancer. For BRCA2, the researchers noted later age at breast cancer diagnosis in women whose mutations were in the OCCR regions, and earlier onset for mutations in the BCCR regions.

Information on age at onset "might have implications for the timing of prevention strategies. If diagnosis would likely be early, around age 30, a woman might be more likely to have oophorectomy than a woman who would be predicted to be diagnosed at age 50 and can maintain fertility as long as possible," said Dr. Rebbeck.

The researchers used hazard risk ratios to derive putative mutation-specific effects on absolute cancer risk, and incorporated published estimates for overall risk for breast cancer by age 70 for carriers of BRCA1 (59%) or BRCA2 (51%) mutations, and for overall risk for ovarian cancer by age 70 for carriers of BRCA1 (34%) or BRCA2 (11%) mutations.

The researchers provided a few risk-change scenarios. For instance, breast cancer risk in BRCA1 mutation carriers rose from 59% to 69% (95% confidence intervals [CI], 56% - 83%) for women with a mis-sense mutation, a founder mutation, or a nonsense mutation resulting in the production of truncated proteins. And ovarian cancer risk in BRCA1 mutation carriers decreased from 34% to 26% (95% CI, 10% - 43%) for women with a founder mutation. For BRCA2, mutations that do not lead to nonsense-mediated decay decrease the risk for ovarian cancer.

This study has several limitations. It did not analyze all mutations, the founder mutations might have been over-represented, and the population involved women who had undergone BRCA1/2 genetic testing, the researchers note.

Dr. Rebbeck has disclosed no relevant financial relationships. Some of his coauthors report financial relationships with a number of pharmaceutical companies or are patent holders, as detailed in the publication.

JAMA. 2015;313:1347-1361. Abstract

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