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author:("ephus, David")
1.  An Internal Performance Assessment of CancerGene Connect: An Electronic Tool to Streamline, Measure and Improve the Genetic Counseling Process 
Journal of genetic counseling  2014;23(6):1034-1044.
CancerGene Connect (CGC) is a web-based program that combines the collection of family and medical history, cancer risk assessment, psychosocial assessment, report templates, a result tracking system, and a patient follow up system. The performance of CGC was assessed in several ways: pre-appointment completion data analyzed for demographic and health variables; a time study to assess overall time per case and to compare the data entry by the genetic counselor compared to the patient, and a measured quality assessment of the program via observation and interview of patients. Prior to their appointment, 52.3% of 2,414 patients completed the online patient questionnaire section of CGC. There were significant differences in completion rates among racial and ethnic groups. County hospital patients were less likely to complete the questionnaire than insured patients (p<0.0001); and likewise uninsured patients and patients with Medicare/Medicaid were less likely to complete the questionnaire than private patients (p<0.0001). The average genetic counseling time per case was 82 minutes, with no significant differences whether the counselor or the patient completed CGC. CGC reduces genetic counselor time by approximately 14%-46% compared to average time per case using traditional risk assessment and documentation methods previously reported. All surveyed users felt the questionnaire was easy to understand. CGC is an effective tool that streamlines workflow, and provides a standardized data collection tool that can be used to evaluate and improve the genetic counseling process.
PMCID: PMC4233159  PMID: 24916850
CancerGene Connect; health care information technology; genetic counseling; hereditary cancer risk assessment; web-based program
2.  Prediction of Cancer Prevention: From Mammogram Screening to Identification of BRCA1/2 Mutation Carriers in Underserved Populations 
EBioMedicine  2015;2(11):1827-1833.
The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence.
We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers.
We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention.
Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.
•We report outcomes from screening underserved populations at mammography for risk of having a hereditary cancer syndrome.•Despite the screening program, discovery of BRCA mutations and prophylactic surgery rates were low in the underserved.•A prototype model used the study's outcomes to predict population cancer reduction and identify how to improve prevention.
This study evaluated 96,055 individuals at mammography for a family history of cancer to identify BRCA mutation carriers who have a genetic predisposition to breast and ovarian cancer.
The level of success in identification of high risk individuals and completion of cancer prevention activities was used to quantify cancer prevention as a result of our screening program.
We observed suboptimal outcomes, especially in the underserved populations, where screening for high risk individuals did not reduce cancer incidence. This study's model can be used for screening programs to find high risk patients and identify ways to improve outcomes for these patients.
PMCID: PMC4740331  PMID: 26870808
Hereditary breast and ovarian cancer syndrome; Population screening; BRCA1/2; Genetic testing; Underserved
3.  Aggressive estrogen-receptor-positive breast cancer arising in patients with elevated body mass index 
Obese women with estrogen receptor (ER)-positive breast cancer may experience worse disease-free and overall survival. We hypothesize that this observation is due to intrinsically aggressive disease and that obesity will be associated with higher histologic grade and Ki67.
A sequential cohort of women with breast cancer diagnosed over 2 years was assembled from institutional tumor registries. Patient and tumor characteristics were abstracted from medical records; those with noninvasive tumors, or lacking body mass index (BMI), Ki67 or histologic grade data, were excluded. Univariate and multivariate analysis was performed to investigate the relationship between markers of aggressive disease (grade and Ki67) and multiple variables associated with obesity. A subgroup analysis was performed to investigate further whether ER and menopausal status influenced associations between BMI and aggressive phenotypes.
Of the 1007 patients initially identified, 668 (68 %) met the eligibility criteria. In univariate analysis, histologic grade and Ki67 were strongly associated with increased BMI, younger age, and African-American race, but less so with diabetes, hypertension, and hyperlipidemia. Multivariate analysis confirmed that higher histologic grade was associated with increased BMI (p = 0.02), and that increased Ki67 was associated with younger age (p = 0.0003) and African-American race (p = 0.002). Additional analysis found that the association between increased BMI and higher-grade tumors was particularly significant in premenopausal women with ER-positive disease.
This study concludes that increased BMI is associated with aggressive-phenotype breast cancer and may be particularly relevant to ER-positive breast cancer developing in premenopausal African-American women.
PMCID: PMC4362999  PMID: 24913910
Breast cancer; Obesity; Aggressive phenotype; Histologic grade; Ki67
4.  Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers 
Molecular cancer therapeutics  2013;12(10):10.1158/1535-7163.MCT-12-0962.
Improving patient outcome by personalized therapy involves a thorough understanding of an agent’s mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs.
PMCID: PMC3807805  PMID: 23883585
Breast cancer; Catalase; Super Oxide Dismutase, β-Lapachone; NADPH quinone oxidoreductase-1; Poly (ADP-ribose) polymerase-1; Programmed necrosis
5.  27-Hydroxycholesterol Promotes Cell-autonomous ER-positive Breast Cancer Growth 
Cell reports  2013;5(3):637-645.
To date estrogen is the only known endogenous estrogen receptor (ER) ligand that promotes ER+ breast tumor growth. We report that the cholesterol metabolite 27-hydroxycholesterol (27HC) stimulates MCF-7 cell xenograft growth in mice. More importantly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to that in cancer-free controls, and tumor 27HC content is further elevated. Increased tumor 27HC is correlated with diminished expression of CYP7B1, the 27HC metabolizing enzyme, and reduced expression of CYP7B1 in tumors is associated with poorer patient survival. Moreover, 27HC is produced by MCF-7 cells and it stimulates cell-autonomous, ER-dependent and GDNF-RET-dependent cell proliferation. Thus, 27HC is a locally-modulated, non-aromatized ER ligand that promotes ER+ breast tumor growth.
PMCID: PMC3950897  PMID: 24210818
6.  Diabetes, Metformin, and Breast Cancer in Postmenopausal Women 
Journal of Clinical Oncology  2012;30(23):2844-2852.
Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.
Patients and Methods
In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.
Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.
Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
PMCID: PMC3826090  PMID: 22689798
7.  Breast Cancer Phenotype in Women with TP53 Germline Mutations: a Li Fraumeni Syndrome Consortium Effort 
Breast cancer research and treatment  2012;133(3):1125-1130.
Breast cancer is the most common tumor in women with Li Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 carriers have recently been reported to more often be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to expand this small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS.
Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutations carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade and hormone receptor status was assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH.
The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22–46). Of the invasive cancers, 84% were positive for ER and/or PR; 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER, and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases.
This report of the phenotype of breast cancers from women with Li Fraumeni syndrome nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in Li Fraumeni syndrome are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may improve outcomes for women with LFS-associated breast cancer.
PMCID: PMC3709568  PMID: 22392042
Breast Cancer; Li Fraumeni Syndrome; TP53 mutations; HER2; hormone receptors
8.  Tamoxifen Downregulates Ets-oncogene Family Members ETV4 and ETV5 in Benign Breast Tissue: Implications for Durable Risk Reduction 
Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials.
Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples.
Tamoxifen downregulated ets-oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis.
A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. Multipotential progenitor cap cells of terminal end buds may be the primary target.
PMCID: PMC3208724  PMID: 21778330
Tamoxifen; Biomarkers; Gene Expression; Proliferation; DNA Methylation
9.  Auto-fluorescence lifetime and light reflectance spectroscopy for breast cancer diagnosis: potential tools for intraoperative margin detection 
Biomedical Optics Express  2012;3(8):1825-1840.
This study investigates the use of two spectroscopic techniques, auto-fluorescence lifetime measurement (AFLM) and light reflectance spectroscopy (LRS), for detecting invasive ductal carcinoma (IDC) in human ex vivo breast specimens. AFLM used excitation at 447 nm with multiple emission wavelengths (532, 562, 632, and 644 nm), at which auto-fluorescence lifetimes and their weight factors were analyzed using a double exponent model. LRS measured reflectance spectra in the range of 500-840 nm and analyzed the spectral slopes empirically at several distinct spectral regions. Our preliminary results based on 93 measured locations (i.e., 34 IDC, 31 benign fibrous, 28 adipose) from 6 specimens show significant differences in 5 AFLM-derived parameters and 9 LRS-based spectral slopes between benign and malignant breast samples. Multinomial logistic regression with a 10-fold cross validation approach was implemented with selected features to classify IDC from benign fibrous and adipose tissues for the two techniques independently as well as for the combined dual-modality approach. The accuracy for classifying IDC was found to be 96.4 ± 0.8%, 92.3 ± 0.8% and 96 ± 1.3% for LRS, AFLM, and dual-modality, respectively.
PMCID: PMC3409702  PMID: 22876347
(170.1610) Clinical applications; (170.3650) Lifetime-based sensing; (170.6935) Tissue characterization; (170.4580) Optical diagnostics for medicine; (170.6510) Spectroscopy, tissue diagnostics
10.  Bootcamp During Neoadjuvant Chemotherapy for Breast Cancer: A Randomized Pilot Trial 
Exercise may improve cancer outcomes. Neoadjuvant chemotherapy (NC) for breast cancer provides a unique setting to evaluate intervention effects. Treatments leading to decreased post-neoadjuvant Ki-67 levels, smaller tumor size, and higher pathologic response are associated with improved survival and lower recurrence. This randomized, prospective pilot trial evaluates the feasibility of supervised exercise during NC for breast cancer.
Stage II-III, ER positive, cancer patients with BMI > 25 receiving NC were randomized to standard NC with supervised bootcamp (NC + BC) or NC alone. Ki-67, C-peptide, BMI, and tumor size were measured before chemotherapy and at time of surgery.
There were no initial differences between groups in regards to tumor size, C-peptide, BMI, and Ki–67. The NC + BC (n = 5) group had a lower mean BMI at the conclusion of NC compared with those (n = 5) in the NC group (28.0 versus 35.8, P = 0.03). Final tumor size was 2.59 cm in the NC + BC group versus 3.16 cm for NC (P = 0.76) Mean Ki-67 for NC + BC was 7% versus 29% with NC (P = 0.14). C-peptide (ng/mL) was equivalent between the two groups (4.55 NC + BC versus 4.74 NC, P = 0.85).
Adding a supervised exercise program to NC is feasible, decreases BMI, and may lead to lower Ki-67 levels and improved survival.
PMCID: PMC3290117  PMID: 22399859
breast cancer; exercise; Ki-67; neoadjuvant chemotherapy
11.  Influence of Surgical Technique on Mastectomy and Reexcision Rates in Breast-Conserving Therapy for Cancer 
Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30–50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates.
PMCID: PMC3265214  PMID: 22312542
12.  Axillary lymph node dissection for breast cancer utilizing Harmonic Focus® 
For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus® will decrease operative time and reduce post-operative complications.
Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study.
Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups.
In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.
PMCID: PMC3170616  PMID: 21843361
13.  RASSF1A Polymorphism A133S Is Associated with Early Onset Breast Cancer in BRCA1/2 Mutation Carriers 
Cancer research  2008;68(1):22-25.
The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in ~50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10–2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06–2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04–3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer patho-genesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.
PMCID: PMC2833356  PMID: 18172292
14.  Identification of 5 novel genes methylated in breast and other epithelial cancers 
Molecular Cancer  2010;9:51.
There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer.
Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; EMILIN2, SALL1, DBC1, FBLN2 and CIDE-A. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of EMILIN2 was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers.
The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.
PMCID: PMC2841122  PMID: 20205715
15.  Validity of Models for Predicting BRCA1 and BRCA2 Mutations 
Annals of internal medicine  2007;147(7):441-450.
Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood.
To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University.
Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models.
Multicenter study across Cancer Genetics Network participating centers.
3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics.
Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions.
The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing.
Three recently published models were not included.
All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations.
PMCID: PMC2423214  PMID: 17909205
16.  Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome 
Identifying families at high risk for the Lynch syndrome (ie, hereditary non-polyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.
To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.
Design, Setting, and Patients
External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993–2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model’s prediction is tailored to each individual’s detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.
Main Outcome Measure
Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.
In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78–0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84–1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.
MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.
PMCID: PMC2538673  PMID: 17003396
17.  Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample 
An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.
We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.
In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.
The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.
PMCID: PMC2323978  PMID: 16484695
18.  A Genome-Wide Screen for Promoter Methylation in Lung Cancer Identifies Novel Methylation Markers for Multiple Malignancies  
PLoS Medicine  2006;3(12):e486.
Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets.
Methods and Findings
In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors.
By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention.
John Minna and colleagues report that a group of genes are commonly methylated in primary lung, breast, colon, and prostate cancer.
Editors' Summary
Tumors or cancers contain cells that have lost many of the control mechanisms that normally regulate their behavior. Unlike normal cells, which only divide to repair damaged tissues, cancer cells divide uncontrollably. They also gain the ability to move round the body and start metastases in secondary locations. These changes in behavior result from alterations in their genetic material. For example, mutations (permanent changes in the sequence of nucleotides in the cell's DNA) in genes known as oncogenes stimulate cells to divide constantly. Mutations in another group of genes—tumor suppressor genes—disable their ability to restrain cell growth. Key tumor suppressor genes are often completely lost in cancer cells. But not all the genetic changes in cancer cells are mutations. Some are “epigenetic” changes—chemical modifications of genes that affect the amount of protein made from them. In cancer cells, methyl groups are often added to CG-rich regions—this is called hypermethylation. These “CpG islands” lie near gene promoters—sequences that control the transcription of DNA into RNA, the template for protein production—and their methylation switches off the promoter. Methylation of the promoter of one copy of a tumor suppressor gene, which often coincides with the loss of the other copy of the gene, is thought to be involved in cancer development.
Why Was This Study Done?
The rules that govern which genes are hypermethylated during the development of different cancer types are not known, but it would be useful to identify any DNA methylation events that occur regularly in common cancers for two reasons. First, specific DNA methylation markers might be useful for the early detection of cancer. Second, identifying these epigenetic changes might reveal cellular pathways that are changed during cancer development and so identify new therapeutic targets. In this study, the researchers have used a systematic biological screen to identify genes that are methylated in many lung, breast, colon, and prostate cancers—all cancers that form in “epithelial” tissues.
What Did the Researchers Do and Find?
The researchers used microarray expression profiling to examine gene expression patterns in several lung cancer and normal lung cell lines. In this technique, labeled RNA molecules isolated from cells are applied to a “chip” carrying an array of gene fragments. Here, they stick to the fragment that represents the gene from which they were made, which allows the genes that the cells express to be catalogued. By comparing the expression profiles of lung cancer cells and normal lung cells before and after treatment with a chemical that inhibits DNA methylation, the researchers identified genes that were methylated in the cancer cells—that is, genes that were expressed in normal cells but not in cancer cells unless methylation was inhibited. 132 of these genes contained CpG islands. The researchers examined the promoters of 45 of these genes in lung cancer cells taken straight from patients and found that 31 of the promoters were methylated in tumor tissues but not in adjacent normal tissues. Finally, the researchers looked at promoter methylation of the eight genes most frequently and specifically methylated in the lung cancer samples in breast, colon, and prostate cancers. Seven of the genes were frequently methylated in both lung and breast cancers; four were extensively methylated in all the tumor types.
What Do These Findings Mean?
These results identify several new genes that are often methylated in four types of epithelial tumor. The observation that these genes are methylated in multiple independent tumors strongly suggests, but does not prove, that loss of expression of the proteins that they encode helps to convert normal cells into cancer cells. The frequency and diverse patterning of promoter methylation in different tumor types also indicates that methylation is not a random event, although what controls the patterns of methylation is not yet known. The identification of these genes is a step toward building a promoter hypermethylation profile for the early detection of human cancer. Furthermore, although tumors in different tissues vary greatly with respect to gene expression patterns, the similarities seen in this study in promoter methylation profiles might help to identify new therapeutic targets common to several cancer types.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Cancer Institute, information for patients on understanding cancer
CancerQuest, information provided by Emory University about how cancer develops
Cancer Research UK, information for patients on cancer biology
Wikipedia pages on epigenetics (note that Wikipedia is a free online encyclopedia that anyone can edit)
The Epigenome Network of Excellence, background information and latest news about epigenetics
PMCID: PMC1716188  PMID: 17194187

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