Clinical significance of large rearrangements in BRCA1 and BRCA2

BACKGROUND:

Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer.

METHODS:

Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as “high‐risk” if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. “Elective” patients did not meet the high‐risk criteria, but underwent LR testing as ordered by the referring health care provider.

RESULTS:

Overall BRCA1/2 mutation prevalence among high‐risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high‐risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high‐risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients.

CONCLUSIONS:

Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. Cancer 2012. © 2012 American Cancer Society.     

BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast‐ovarian cancer

BACKGROUND:

In women at increased risk for breast and ovarian cancer, the identification of a mutation in breast cancer gene 1 (BRCA1) and BRCA2 has important implications for screening and prevention counseling. Uncertainty regarding the role of BRCA1 and BRCA2 testing in high‐risk women from diverse ancestral backgrounds exists because of variability in prevalence estimates of deleterious (disease‐associated) mutations in non‐white populations. In this study, the authors examined the prevalence of BRCA1 and BRCA2 mutations in an ethnically diverse group of women who were referred for genetic testing.

METHODS:

In this cross‐sectional analysis, the prevalence of BRCA1 and BRCA2 mutations was assessed in a group of non‐Ashkenazi Jewish women who underwent genetic testing.

RESULTS:

From 1996 to 2006, 46,276 women who met study criteria underwent DNA full‐sequence analysis of the BRCA1 and BRCA2 genes. Deleterious mutations were identified in 12.5% of women, and recurrent deleterious mutations (prevalence >2%) were identified in all ancestral groups. Women of non‐European descent were younger (mean age, 45.9 years; standard deviation [SD], 11.6 years) than European women (mean age, 50 years; SD, 11.9 years; P < .001). Women of African (15.6%; odds ratio [OR], 1.3 [95% confidence interval (95% CI), 1.1‐1.5]) and Latin American (14.8%; OR, 1.2 [95% CI, 1.1‐1.4]) ancestries had a significantly higher prevalence of deleterious BRCA1 and BRCA2 mutations compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in those 2 groups. Non‐European ethnicity was associated strongly with having a variant of uncertain significance; however, reclassification decreased variant reporting (from 12.8%→5.9%), and women of African ancestry experienced the largest decline (58%).

CONCLUSIONS:

Mutation prevalence was found to be high among women who were referred for clinical BRCA1 and BRCA2 testing, and the risk was similar across diverse ethnicities. BRCA1 and BRCA2 testing is integral to cancer risk assessment in all high‐risk women. Cancer 2009. © 2009 American Cancer Society.     

The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer

Background:

Men with a BRCA2 mutation face an increased risk of prostate cancer. These cancers tend to have an aggressive nature and it has not yet been demonstrated that regular screening of BRCA2 carriers is associated with improved survival.

Methods:

We identified 4187 men who underwent a prostate cancer biopsy for an elevated PSA or an abnormal digital rectal examination between 1998 and 2010. We screened the BRCA2 gene in its entirety for mutations and we followed the men for death from prostate cancer until December 2012.

Results:

The 12-year prostate cancer-specific survival rate was 94.3% for men without a BRCA2 mutation and was 61.8% for men with a mutation (P<10⁻⁴; log-rank test).

Conclusions:

The survival of men with screen-detected prostate cancer and a BRCA2 mutation is much poorer than expected.     

Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer

BACKGROUND:

Multiple observational studies have suggested that breast cancer gene (BRCA)‐associated ovarian cancers have improved survival compared with BRCA‐negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1‐associated and BRCA2‐associated ovarian cancers were associated with different outcomes.

METHODS:

This was a single‐institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who underwent BRCA mutation testing on 1 of 2 institutional review board‐approved follow‐up studies. Patients who had been tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients who were referred for genetic testing because of long survival.

RESULTS:

Data from 190 patients (143 BRCA‐negative patients, 30 BRCA1‐positive patients, and 17 BRCA2‐positive patients) were analyzed. During the study period, 73 deaths were observed (60 BRCA‐negative patients, 10 BRCA1‐positive patients, 3 BRCA2‐positive patients). The median follow‐up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA‐negative patients, BRCA1‐positive patients, and BRCA2‐positive patients were alive, respectively. On univariate analysis, age, BRCA2 mutations, debulking status, and type of first‐line therapy (intravenous or intraperitoneal) were significant predictors of overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06‐0.65; P = .007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36‐1.38; P = .31), predicted for improved overall survival compared with BRCA‐negative patients. When carriers of BRCA2 mutations were directly compared with carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% confidence interval, 0.08‐1.05; P = .060), although this finding did not reach significance.

CONCLUSIONS:

The current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA‐negative or having a BRCA1 mutation in high‐grade serous ovarian cancer. This finding may have important implications for clinical trial design. Cancer 2012. © 2011 American Cancer Society.     

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

BACKGROUND:

Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain.

METHODS:

Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia–BRCA pathway. Ten cases with < 10% serous histology were also assessed.

RESULTS:

Seven subjects (4.6%) carried germline loss‐of‐function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li‐Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history.

CONCLUSIONS:

Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations. Cancer 2013. © 2012 American Cancer Society.     

Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer

BACKGROUND:

This study assessed BRCA1 and BRCA2 mutation prevalence in an unselected cohort of patients with triple‐negative breast cancer (BC).

METHODS:

One hundred ninety‐nine patients were enrolled. Triple negativity was defined as <1% estrogen and progesterone staining by immunohistochemistry and HER‐2/neu not overexpressed by fluorescence in situ hybridization. Having given consent, patients had BRCA1 and BRCA2 full sequencing and large rearrangement analysis. Mutation prevalence was assessed among the triple‐negative BC patients and the subset of patients without a family history of breast/ovarian cancer. Independent pathological review was completed on 50 patients.

RESULTS:

Twenty‐one deleterious BRCA mutations were identified—13 in BRCA1 and 8 in BRCA2 (prevalence, 10.6%). In 153 patients (76.9%) without significant family history (first‐degree or second‐degree relatives with BC aged <50 years or ovarian cancer at any age), 8 (5.2%) mutations were found. By using prior National Comprehensive Cancer Network (NCCN) guidelines recommending testing for triple‐negative BC patients aged <45 years, 4 of 21 mutations (19%) would have been missed. Two of 21 mutations (10%) would have been missed using updated NCCN guidelines recommending testing for triple‐negative BC patients aged <60 years.

CONCLUSIONS:

The observed mutation rate was significantly higher (P = .0005) than expected based on previously established prevalence tables among patients unselected for pathology. BRCA1 mutation prevalence was lower, and BRCA2 mutation prevalence was higher, than previously described. Additional mutation carriers would have met new NCCN testing guidelines, underscoring the value of the updated criteria. Study data suggest that by increasing the age limit to 65 years, all carriers would have been identified. Cancer 2011;. © 2011 American Cancer Society.     

Contribution of BRCA1 germ-line mutations to breast cancer in Greece: a hospital-based study of 987 unselected breast cancer cases

Background:

In most Western populations, 5–10% of all breast cancer cases can be attributed to major genetic factors such as predisposing mutations in BRCA1 and BRCA2, with early-onset cases generally considered as an indicator of genetic susceptibility. Specific BRCA1 and BRCA2 mutations or different mutation frequencies have been identified in specific populations and ethnic groups. Previous studies in Greek breast and/or ovarian cancer patients with family history have shown that four specific BRCA1 mutations, c.5266dupC, G1738R, and two large genomic rearrangements involving deletions of exons 20 and 24, have a prominent function in the population''s BRCA1 and BRCA2 mutation spectrum.

Methods:

To estimate the frequency of the above mutations in unselected Greek breast cancer women, we screened 987 unselected cases independently of their family history, collected from major Greek hospitals.RESULTS: Of the 987 patients, 26 (2.6%) were found to carry one of the above mutations in the BRCA1 gene: 13 carried the c.5266dupC mutation (1.3%), 6 carried the exon 24 deletion (0.6%), 3 carried the exon 20 deletion (0.3%), and 4 carried the G1738R mutation (0.4%). Among 140 patients with early-onset breast cancer (<40 years), 14 carried one of the four mutations (10.0%).

Conclusion:

These results suggest that a low-cost genetic screening for only the four prominent BRCA1 mutations may be advisable to all early-onset breast cancer patients of Greek origin.     

Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non–clinic‐based sample of women in northern California

BACKGROUND:

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk‐reducing salpingo‐oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women.

METHODS:

White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non–clinic‐based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan‐Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses.

RESULTS:

The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P < .001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03‐5.45) and was 3.98 (95% confidence interval, 2.87‐5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027).

CONCLUSIONS:

The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers. Cancer 2013. © 2012 American Cancer Society.     

Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer

BACKGROUND:

Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast‐pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.

METHODS:

A clinical database review (2000‐2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first‐, second‐, or third‐degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed‐to‐expected (O:E) mutation prevalence was calculated for the entire group.

RESULTS:

Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first‐, second‐, or third‐degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15).

CONCLUSIONS:

BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast‐pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence. Cancer 2011;. © 2011 American Cancer Society.     

Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation

Background:

The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient''s tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation.

Methods:

A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient''s tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT–PCR. Tumour response to standard chemotherapies was evaluated.

Results:

Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments.

Conclusions:

This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.     

Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ

BACKGROUND:

It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high‐risk variables. The authors of this report identified predictive factors for mutations in the breast cancer‐susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS.

METHODS:

One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status.

RESULTS:

Of 118 high‐risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations. Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. In a multivariate logistic model, ≥2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38‐56.29; P = .034), and a score ≥10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23‐18.22; P = .0005) remained as independent significant predictors for a BRCA mutation. Fifty‐seven percent of mutation carriers but only 25% of noncarriers underwent prophylactic mastectomy(P = .0037). This difference remained significant for patients aged ≤40 years (P = .025).

CONCLUSIONS:

Women who had DCIS and a family history of OC or who had BRCAPRO scores ≥10% had a high rate of BRCA positivity regardless of age at diagnosis. These findings suggest that high‐risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer. Cancer 2011;. © 2011 American Cancer Society.     

Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study

Background:

The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes.

Methods:

We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person–years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries.

Results:

Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54–1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30–1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77–7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33–1.00) for women aged 50 years and above.

Conclusion:

The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.     

BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

Background:

Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing.

Methods:

We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts.

Results:

We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients.

Discussion:

We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.     

Cost‐effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers

BACKGROUND:

Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines.

METHODS:

A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers. Three dual‐modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6‐month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6‐month intervals beginning at age 30 years (Alt30). Primary outcomes were quality‐adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost‐effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs).

RESULTS:

All 3 dual‐modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False‐positive test results increased substantially with dual‐modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up‐front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs.

CONCLUSIONS:

Alternating MRI and DM screening at 6‐month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost‐effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers. Cancer 2013. © 2012 American Cancer Society.     

Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations

BACKGROUND:

Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

METHODS:

The authors reviewed the medical histories of 6052 women with a BRCA1 or BRCA2 mutation, half of whom had been diagnosed with breast cancer. They estimated the odds ratio for breast cancer, given a self‐report of diabetes. They then estimated the hazard ratio for a new diagnosis of diabetes associated with a history of breast cancer.

RESULTS:

There was no excess of diabetes in the period before the diagnosis of breast cancer, compared with controls with no diagnosis of breast cancer. The risk of diabetes was doubled among BRCA carriers in the 15‐year period after the diagnosis of breast cancer (relative risk, 2.0; 95% confidence interval [CI], 1.4‐2.8; P = .0001), compared with carriers without cancer. The risk was particularly high for women with a body mass index (BMI) >25.0 kg/m² (odds ratio, 5.8; 95% CI, 4.0‐8.6; P = .0001).

CONCLUSIONS:

After a diagnosis of breast cancer, women with a BRCA1 or BRCA2 mutation face a 2‐fold increase in the risk of diabetes, which is exacerbated by a high BMI. Cancer 2011. © 2010 American Cancer Society.     

Bone‐induced c‐kit expression in prostate cancer: A driver of intraosseous tumor growth

Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c‐kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c‐kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c‐kit expression promotes migration and invasion of PCa cells. Alongside, we found that c‐kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c‐kit‐transfected PCa cells resulted in reduction of c‐kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c‐kit. The inverse association between c‐kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone‐induced c‐kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone‐induced c‐kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis.     

Accuracy of the BRCAPRO model among women with bilateral breast cancer

BACKGROUND:

The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis.

METHODS:

A retrospective chart review was performed. Women who were diagnosed with bilateral or unilateral breast cancer and who had undergone comprehensive BRCA1 and BRCA2 genetic testing at M. D. Anderson Cancer Center between 1997 and 2006 were included in the study.

RESULTS:

For individuals with pre‐test carrier probabilities >31%, the proportion of positive tests was significantly lower than predicted by the BRCAPRO model (P < .05). In addition, the carrier rate of BRCA mutations was significantly higher (P = .002, Fisher exact test) in women with bilateral breast cancer whose age at first diagnosis was ≤40 years compared with those diagnosed >40 years.

CONCLUSIONS:

The BRCAPRO model was overestimating the relative contribution bilateral breast cancer had on the likelihood of detecting a BRCA1 or BRCA2 mutation. Bilateral breast cancer did not appear to be a good indicator of mutation status, particularly for women whose age at first diagnosis is >40 years. Cancer 2009. © 2009 American Cancer Society.     

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital‐based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt (“discovery series”); and 422 women diagnosed after age 40 and with negative family history (“older‐onset sporadic patient series”). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, nonfamilial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in 11 different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (p = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (p = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li‐Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling.     

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation‐negative familial ovarian cancers

BACKGROUND:

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC‐related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

METHODS:

Seventy‐seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC‐associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.

RESULTS:

None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious.

CONCLUSIONS:

HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing. Cancer 2009. © 2009 American Cancer Society.     

High detection rate for BRCA2 mutations in male breast cancer families from North West England

33 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA2 mutations. 12 pathogenic BRCA2 mutations were identified (36%) in samples from an affected family member. All mutations segregated with disease where it was possible to check. Of the 14 families fulfilling BCLC criteria, 9 (64%) had mutations whilst only 3/16 (19%) of male breast cancer patients with less significant female breast cancer family history having a mutation. All 3 families with ovarian cancer and 3 families with multiple male breast cancer cases had BRCA2 mutations. These data are a further guide to how to prioritise samples for BRCA2 mutation analysis.