Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Associations between single nucleotide polymorphisms in double-stranded DNA repair pathway genes and familial breast cancer.

PURPOSE: DNA damage recognition and repair play a major role in risk for breast cancer. We investigated 104 single nucleotide polymorphisms (SNP) in 17 genes whose protein products are involved in double-stranded break repair (DSBR). EXPERIMENTAL DESIGN: We used a case-control design. Both the case individuals affected with breast cancer or with both breast and ovarian cancers and the controls had similar familial risk of breast cancer and were participants in a high-risk cancer registry. RESULTS: We found that 12 of the polymorphisms are associated with breast or breast and ovarian cancers, most notably rs16888927, rs16888997, and rs16889040, found in introns of RAD21, suggesting that SNPs in other genes in the DSBR pathway in addition to BRCA1 and BRCA2 may affect breast cancer risk. CONCLUSIONS: SNPs within or near several DSBR DNA repair pathway genes are associated with breast cancer in individuals from a high-risk population. In addition, our study reemphasizes the unique perspective that recruitment of cases and controls from family cancer registries has for gene discovery studies.

The trajectory of psychological impact in BRCA1/2 genetic testing: does time heal?

BACKGROUND: Most research on adjustment of women undergoing genetic testing for breast cancer susceptibility has not followed women for more than 6 months after result receipt and has not evaluated curvilinear patterns in general and cancer-specific adjustment. PURPOSE: This study's primary goal was to examine the trajectory of psychological status in women at risk for breast and ovarian cancer prior to undergoing genetic testing through 1 year after BRCA1/2 result receipt. METHODS: Women in the UCLA Familial Cancer Registry completed questionnaires assessing psychological status (i.e., depressive symptoms, negative and positive mood, anxiety, and cancer-related distress) prior to testing and at 1, 6, and 12 months after result receipt. RESULTS: Of 155 women tested, 117 were BRCA1/2- (96 uninformative negative and 21 true negative) and 38 were BRCA1/2+. Linear mixed model analyses revealed a consistent pattern in adjustment indicators, such that the groups did not differ at baseline, but mutation carriers endorsed significantly more depressive symptoms, negative mood, and cancer-specific distress relative to non-mutation carriers at 1 and 6 months after test result receipt (and less positive mood at 6 months only). At 12 months, negative and positive mood returned to baseline levels for mutation carriers, and depressive symptoms approached baseline. At 12 months, the groups differed significantly only on cancer-specific distress, owing to declining distress in non-carriers. Neither having a previous cancer diagnosis nor receiving a true negative versus uninformative negative result predicted reactions to genetic testing. CONCLUSIONS: Genetic testing prompted an increase in general and cancer-specific distress for BRCA1/2+ women, which remitted by 1 year after result receipt.

Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO.

BACKGROUND: Because BRCA gene mutation testing is costly, occasionally uninformative, and frequently associated with ethical and legal issues, careful patient selection is required prior to testing. Estimation of BRCA gene mutation probability is an important component of pretest counseling, but the accuracy of these estimates is currently unknown. We measured the performance of eight cancer risk counselors and of a computer model, BRCAPRO, at identifying families likely to carry a BRCA gene mutation. METHODS: Eight cancer risk counselors and the computer model BRCAPRO estimated BRCA gene mutation probabilities for 148 pedigrees selected from an initial sample of 272 pedigrees. The final sample was limited to pedigrees with a proband affected by breast or ovarian cancer and BRCA1 and BRCA2 gene sequencing results unequivocally reported as negative or positive for a deleterious mutation. Sensitivity, specificity, negative predictive value, positive predictive value, and areas under receiver operator characteristics (ROC) curves were calculated for each risk counselor and for BRCAPRO. All statistical tests were two sided. RESULTS: Using a greater-than-10% BRCA gene mutation probability threshold, the median sensitivity for identifying mutation carriers was 94% (range = 81% to 98%) for the eight risk counselors and 92% (range = 91% to 92%) for BRCAPRO. Median specificity at this threshold was 16% (range = 6% to 34%) for the risk counselors and 32% (range = 30% to 34%) for BRCAPRO (P =.04). Median area under the ROC curves was 0.671 for the risk counselors (range = 0.620 to 0.717) and 0.712 (range = 0.706 to 0.720) for BRCAPRO (P =.04). There was a slight, but not statistically significant, improvement in all counselor performance measures when BRCAPRO-assigned gene mutation probability information was included with the pedigrees. CONCLUSIONS: Sensitivity for identifying BRCA gene mutation carriers is similar for experienced risk counselors and the computer model BRCAPRO. Because the computer model consistently demonstrated superior specificity, overall discrimination between BRCA gene mutation carriers and BRCA gene mutation noncarriers was slightly better for BRCAPRO.

Benefit finding in response to BRCA1/2 testing.

BACKGROUND: Undergoing genetic testing for BRCA1/2 mutations may be accompanied by elevated worry and distress, but the potential for the experience to catalyze positive psychological and life changes has not been studied. PURPOSE: This study was designed to examine the relationship between mutation carrier status, personal cancer history, and the potential positive impact of genetic testing (i.e., benefit finding). We also tested two predictors of benefit finding (BF) derived from the theoretical and empirical literature on positive outcomes of stress: impact of the experience and approach-oriented coping. METHODS: Women undergoing genetic testing for BRCA1/2 mutations (n = 108) completed questionnaires assessing test-related distress, approach-oriented coping, and BF after receipt of test results. BRCA1/2 status was determined from genetic test results and personal cancer history from interviews conducted with study participants before testing. RESULTS: Reports of BF in this sample were highly variable, as some women did not perceive the testing experience as having any noticeable effect on their lives, whereas others reported positive changes similar to those observed in cancer patients (e.g., significantly improved relationships, greater appreciation for life). Contrary to hypotheses, women who tested positive for BRCA1/2 did not report higher levels of BF in response to genetic testing than those who tested negative. However, BF scores were elevated among mutation carriers who had a previous cancer diagnosis. As predicted, test-related distress and approach-oriented coping were also positively associated with BF, and approach-oriented coping mediated the relationship between carrier status x cancer history and BF. CONCLUSIONS: Findings suggest that positive life changes can occur among women who test positive for BRCA1/2 mutations, particularly cancer survivors.

Pro-inflammatory cytokines and depression in a familial cancer registry.

Patients undergoing cancer treatment (e.g., interferon or IL-2 treatment) develop depression, and there is a positive relationship between their depression and circulating levels of proinflammatory cytokines. Depressed patients who are medically healthy also show increases in circulating markers of inflammation. The present study characterized baseline levels of inflammatory cytokine activity in 18 pairs of depressed and non-depressed persons at high risk for cancer and matched for age, ethnicity and all unaffected by a personal history of cancer. Circulating levels of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha-receptor (TNF-RII), and soluble intercellular adhesion molecule (sICAM) did not differ between those with and without depression. The present data are important for characterizing persons at high risk for cancer who may later acquire knowledge of further increased risk through genetic testing.