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Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use.

https://arctichealth.org/en/permalink/ahliterature164157
Source
Carcinogenesis. 2007 Oct;28(10):2139-42
Publication Type
Article
Date
Oct-2007
Author
William Chu
Anthony Fyles
Edward M Sellers
David R McCready
Joan Murphy
Tuya Pal
Steven A Narod
Author Affiliation
Department of Radiation Oncology, Princess Margaret Hospital-University Health Network, Toronto, Ontario, Canada.
Source
Carcinogenesis. 2007 Oct;28(10):2139-42
Date
Oct-2007
Language
English
Publication Type
Article
Keywords
Adult
Breast Neoplasms - drug therapy
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - genetics
Endometrial Neoplasms - chemically induced - epidemiology - genetics
Female
Genotype
Humans
Odds Ratio
Ontario
Postmenopause
Premenopause
Registries
Retrospective Studies
Selective Estrogen Receptor Modulators - adverse effects
Tamoxifen - adverse effects
Abstract
Tamoxifen is a selective estrogen receptor modulator that is used to treat and to prevent breast cancer; however, its use is associated with an increased risk of endometrial cancer. Tamoxifen is metabolized by various cytochrome P450 (CYP) enzymes, but predominantly by CYP3A4. In this study, we examined whether a genetic variant of the CYP3A4 gene, CYP3A4*1B, influences endometrial cancer risk--alone and when associated with tamoxifen exposure. We conducted a case-control study on 566 endometrial cancer cases and 964 ethnically matched controls. The variant CYP3A4 allele was present in 6% of the controls and 9% of the endometrial cancer patients (OR = 1.6, 95% CI = 1.1-2.3, P = 0.02). The allele was more common in women with endometrial cancer who had been treated with tamoxifen for breast cancer (16%). Women who carried the CYP3A4*1B allele had approximately 3-fold increase in the risk of developing endometrial cancer following tamoxifen treatment, compared with women who did not take tamoxifen (P = 0.004). These findings suggest that a subgroup of breast cancer patients who carry the CYP3A4*1B allele and take tamoxifen may be at increased risk of developing endometrial cancer.
PubMed ID
17434921 View in PubMed
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Association between germline HOXB13 G84E mutation and risk of prostate cancer.

https://arctichealth.org/en/permalink/ahliterature122735
Source
J Natl Cancer Inst. 2012 Aug 22;104(16):1260-2
Publication Type
Article
Date
Aug-22-2012
Author
Mohammad R Akbari
John Trachtenberg
Justin Lee
Stephanie Tam
Robert Bristow
Andrew Loblaw
Steven A Narod
Robert K Nam
Author Affiliation
Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.
Source
J Natl Cancer Inst. 2012 Aug 22;104(16):1260-2
Date
Aug-22-2012
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Biopsy
Canada
Case-Control Studies
European Continental Ancestry Group - genetics
Genetic Predisposition to Disease
Germ-Line Mutation
Homeodomain Proteins - genetics
Humans
Male
Middle Aged
Odds Ratio
Prostatic Neoplasms - genetics
Research Design
Risk assessment
Risk factors
Abstract
Recently, a G84E mutation in HOXB13, a gene involved in prostate development, was shown to be strongly associated with an increased risk of prostate cancer. To confirm this association in a screening setting, we conducted a case-control study and sequenced germline DNA from peripheral leukocytes of 1843 men diagnosed with prostate cancer (case subjects) and 2225 men without prostate cancer (control subjects) for mutations in HOXB13. Subjects (aged 40-94 years) were prescreened and underwent a prostate biopsy at two tertiary care centers in Canada. The frequency of HOXB13 variants was determined in case subjects and control subjects by race, and odds ratios and 95% confidence intervals were based on 2×2 table analysis. All statistical tests were two-sided. Twelve men of white race were identified to be carriers of the G84E mutation. The G84E mutation was more frequent among white case subjects than among white control subjects (10 of 1525 [0.7%] vs 2 of 1757 [0.1%], P = .01) and was associated with an increased risk of prostate cancer (unadjusted odds ratio = 5.8, 95% confidence interval = 1.3 to 26.5, P = .01).
Notes
Comment In: J Urol. 2013 Feb;189(2):52823312158
PubMed ID
22781434 View in PubMed
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A BRCA1 mutation in Native North American families.

https://arctichealth.org/en/permalink/ahliterature190711
Source
Hum Mutat. 2002 Apr;19(4):460
Publication Type
Article
Date
Apr-2002
Author
Alexander Liede
Elaine Jack
Robert A Hegele
Steven A Narod
Author Affiliation
University of Toronto and Sunnybrook & Women's College, Health Sciences Centre, Toronto, Canada. alex.liede@swchsc.on.ca
Source
Hum Mutat. 2002 Apr;19(4):460
Date
Apr-2002
Language
English
Publication Type
Article
Keywords
Alleles
Breast Neoplasms - genetics
DNA Mutational Analysis
Female
Genes, BRCA1
Genetic Testing
Humans
Indians, North American - genetics
Male
Manitoba
Middle Aged
Mutation - genetics
Ovarian Neoplasms - genetics
Pedigree
Saskatchewan
Abstract
Germline mutations in the BRCA1 (MIM 113705) and BRCA2 (MIM 600185) genes have been identified for breast and ovarian cancer families of diverse ethnic backgrounds. To date, there have been no reports of Native North American families with mutations in BRCA1 or BRCA2. Here we report two families of aboriginal descent both with the same BRCA1 alterations (1510insG, 1506A>G). The families represent two aboriginal Canadian tribes (Cree and Ojibwe), although a common ancestral origin is likely. This is the first evidence of a BRCA1 mutation specific to aboriginal peoples of North America.
PubMed ID
11933205 View in PubMed
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The BRCA2 c.9004G>A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent.

https://arctichealth.org/en/permalink/ahliterature130988
Source
Breast Cancer Res Treat. 2012 Jan;131(1):333-40
Publication Type
Article
Date
Jan-2012
Author
Stephanie Cote
Suzanna L Arcand
Robert Royer
Serge Nolet
Anne-Marie Mes-Masson
Parviz Ghadirian
William D Foulkes
Marc Tischkowitz
Steven A Narod
Diane Provencher
Patricia N Tonin
Author Affiliation
Service de Médecine Génique, Département de Médecine, Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
Source
Breast Cancer Res Treat. 2012 Jan;131(1):333-40
Date
Jan-2012
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Amino Acid Substitution - genetics
BRCA2 Protein - genetics
Breast - pathology
Breast Neoplasms - genetics - pathology
Canada
DNA Mutational Analysis
European Continental Ancestry Group - genetics
Female
Founder Effect
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Middle Aged
Ovarian Neoplasms - genetics - pathology
Pedigree
Polymorphism, Single Nucleotide
Sequence Alignment
Abstract
Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35-55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28-84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.
Notes
Erratum In: Breast Cancer Res Treat. 2012 Jan;131(1):341
PubMed ID
21947752 View in PubMed
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Breast cancer risk perception among women who have undergone prophylactic bilateral mastectomy.

https://arctichealth.org/en/permalink/ahliterature188143
Source
J Natl Cancer Inst. 2002 Oct 16;94(20):1564-9
Publication Type
Article
Date
Oct-16-2002
Author
Kelly A Metcalfe
Steven A Narod
Author Affiliation
The Centre for Research in Women's Health, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario, Canada.
Source
J Natl Cancer Inst. 2002 Oct 16;94(20):1564-9
Date
Oct-16-2002
Language
English
Publication Type
Article
Keywords
Breast Neoplasms - epidemiology - genetics - prevention & control - psychology - surgery
Female
Genes, BRCA1
Genes, BRCA2
Humans
Mastectomy
Medical History Taking
Mutation
Ontario - epidemiology
Perception
Primary prevention - methods
Risk assessment
Abstract
Prophylactic bilateral mastectomy is a preventive option for women who are at high risk of developing breast cancer. We compared the perceptions of breast cancer risk among women who had previously undergone prophylactic bilateral mastectomy with objective estimates of their breast cancer risk.
We asked 75 women in the Canadian province of Ontario who had undergone prophylactic bilateral mastectomy between 1991 and 2000 to provide a complete family history of the cancers that had occurred by the time of their surgery and to indicate their BRCA1 and BRCA2 gene mutation status. This information was used to generate estimates of each woman's risk for breast cancer by using the Gail model, the Claus model, and the BRCAPRO model. Sixty of the women also provided their own estimates of their lifetime risks of developing breast cancer before and after they had prophylactic mastectomy. Risk estimates were compared using Wilcoxon's signed-rank test and Pearson's product-moment correlation analysis. All statistical tests were two-sided.
The women estimated that their lifetime risk of developing breast cancer before surgery was, on average, 76% (range = 20%-100%) and after surgery was 11.4% (range = 0%-60%). The mean estimated absolute risk reduction the women attributed to prophylactic mastectomy was 64.8%. The average computer-generated risk estimates were 59% for the 14 women who reported that they carried a BRCA1 or BRCA2 gene mutation and 17% for the other women (of whom 43 had a strong family history of breast cancer and 18 had a limited family history). Breast cancer risk was statistically significantly overestimated by all women except for the known BRCA1 and BRCA2 gene mutation carriers.
Women who undergo prophylactic bilateral mastectomy have an exaggerated perception of their breast cancer risk before surgery. Formal genetic counseling and genetic testing may result in more accurate risk perceptions to guide women in choosing other preventive options.
PubMed ID
12381709 View in PubMed
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Breast tissue organochlorine levels and metabolic genotypes in relation to breast cancer risk Canada.

https://arctichealth.org/en/permalink/ahliterature180138
Source
Cancer Causes Control. 2004 May;15(4):399-418
Publication Type
Article
Date
May-2004
Author
David McCready
Kristan J Aronson
William Chu
Wenli Fan
Danny Vesprini
Steven A Narod
Author Affiliation
Department of Surgery, University Health Network, Toronto, Ontario, Canada.
Source
Cancer Causes Control. 2004 May;15(4):399-418
Date
May-2004
Language
English
Publication Type
Article
Keywords
Adult
Aged
Alleles
Breast - chemistry
Breast Neoplasms - chemically induced - etiology - genetics
Carcinogens - adverse effects - metabolism
Case-Control Studies
Confidence Intervals
Environmental Exposure - adverse effects
Environmental Pollutants - adverse effects
Female
Genetic Variation
Genotype
Glutathione Transferase - genetics - metabolism
Humans
Hydrocarbons, Chlorinated
Insecticides - adverse effects - metabolism
Middle Aged
Odds Ratio
Ontario - epidemiology
Risk assessment
Risk factors
Abstract
Genes that metabolize the rate of clearance of environmental carcinogens may be candidate genes for cancer susceptibility. There is some data to suggest that exposure to environmental pesticides and other organochlorine pollutants is a risk factor to breast cancer. It is therefore reasonable to ask if variants in the genes responsible for the metabolic activation of organochlorines are associated with different tissue burdens of organochlorines and if these variants modify the risk of breast cancer in the population. We conducted a case-control study of women who underwent an excision biopsy for suspected breast cancer in a Toronto hospital from 1995 to 1997. Patients are residents of the Greater Toronto Area and are primarily Caucasian of European descent. Cases were women with invasive breast cancer (n = 70) and controls (n = 69) were women diagnosed with benign disease, frequency matched by age to cases. Levels of organochlorines were measured in benign breast tissue and seven polymorphisms in five candidate genes were genotyped. In general, women who carried inactive alleles of the GSTM1 had higher levels of breast organochlorines, and were at modestly increased risk of breast cancer (odds ratio = 2.2; 95% CI = 1.1-4.4). However, multiple comparisons were made and generally our data do not support the hypothesis that organochlorines increase the risk of breast cancer among subgroups of women with specific metabolic genotypes.
PubMed ID
15141140 View in PubMed
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Can we select individuals with low risk ductal carcinoma in situ (DCIS)? A population-based outcomes analysis.

https://arctichealth.org/en/permalink/ahliterature115891
Source
Breast Cancer Res Treat. 2013 Apr;138(2):581-90
Publication Type
Article
Date
Apr-2013
Author
Eileen Rakovitch
Sharon Nofech-Mozes
Steven A Narod
Wedad Hanna
Deva Thiruchelvam
Refik Saskin
Carole Taylor
Alan Tuck
Sandip Sengupta
Leela Elavathil
Prashant A Jani
Susan J Done
Naomi Miller
Bruce Youngson
Iwa Kong
Lawrence Paszat
Author Affiliation
Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada. eileen.rakovitch@sunnybrook.ca
Source
Breast Cancer Res Treat. 2013 Apr;138(2):581-90
Date
Apr-2013
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Breast Neoplasms - epidemiology - radiotherapy - surgery
Carcinoma, Intraductal, Noninfiltrating - epidemiology - radiotherapy - surgery
Cohort Studies
Disease-Free Survival
Female
Humans
Incidence
Mastectomy, Segmental
Middle Aged
Neoplasm Recurrence, Local - epidemiology - prevention & control
Ontario - epidemiology
Population
Risk
Treatment Outcome
Young Adult
Abstract
Ductal carcinoma in situ (DCIS), a non-invasive breast cancer, is usually treated by breast-conserving surgery (BCS). Randomized trials prove that the addition of radiotherapy (XRT) leads to lower rates of recurrence. Despite the evidence, half of women do not receive XRT after BCS. It is unknown how well clinicians identify women with low risk DCIS for treatment by BCS alone or to what extent women with DCIS develop recurrent cancer due to the omission of radiotherapy. We report the outcomes of a population of women with DCIS treated with BCS, alone or with radiotherapy, and evaluate the effectiveness of each therapeutic approach. All women diagnosed with DCIS and treated with BCS, alone or with radiotherapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were validated by chart review. Survival analyses were used to study the development of local recurrence (LR) in relation to patient and tumor characteristics and the use of radiotherapy. The cohort included 3,762 women treated with breast-conserving therapy; 1,895 of whom (50 %) also received radiation. At 10 years median follow-up, LR developed in 233 (12 %) women who received radiotherapy and in 363 (19 %) of women who did not (p 
PubMed ID
23456231 View in PubMed
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Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

https://arctichealth.org/en/permalink/ahliterature130807
Source
J Med Genet. 2011 Nov;48(11):783-6
Publication Type
Article
Date
Nov-2011
Author
Mohammad R Akbari
Shiyu Zhang
Isabel Fan
Robert Royer
Song Li
Harvey Risch
John McLaughlin
Barry Rosen
Ping Sun
Steven A Narod
Author Affiliation
Women's College Research Institute, University of Toronto, Toronto, ON, Canada.
Source
J Med Genet. 2011 Nov;48(11):783-6
Date
Nov-2011
Language
English
Publication Type
Article
Keywords
Age Factors
Aged
Aged, 80 and over
BRCA1 Protein - genetics
BRCA2 Protein - genetics
Breast Neoplasms - diagnosis - genetics - mortality
Canada - epidemiology
Cohort Studies
DNA Mutational Analysis
Female
Genetic Predisposition to Disease
Humans
Incidence
Middle Aged
Mutation
Ovarian Neoplasms - diagnosis - genetics - mortality
Pedigree
Penetrance
Probability
Prognosis
Risk factors
Survival Analysis
Abstract
Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p
PubMed ID
21965345 View in PubMed
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Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis.

https://arctichealth.org/en/permalink/ahliterature104996
Source
BMJ. 2014;348:g226
Publication Type
Article
Interactive/Multimedia
Date
2014
Author
Kelly Metcalfe
Shelley Gershman
Parviz Ghadirian
Henry T Lynch
Carrie Snyder
Nadine Tung
Charmaine Kim-Sing
Andrea Eisen
William D Foulkes
Barry Rosen
Ping Sun
Steven A Narod
Author Affiliation
Lawrence S Bloomberg Faculty of Nursing, University of Toronto, Canada.
Source
BMJ. 2014;348:g226
Date
2014
Language
English
Publication Type
Article
Interactive/Multimedia
Keywords
Adult
BRCA1 Protein - genetics - metabolism
BRCA2 Protein - genetics - metabolism
Breast Neoplasms - genetics - mortality - surgery
Canada - epidemiology
DNA, Neoplasm - genetics
Female
Forecasting
Humans
Mastectomy - methods - mortality
Middle Aged
Mutation
Neoplasm Staging
Retrospective Studies
Survival Rate - trends
United States - epidemiology
Abstract
To compare the survival rates of women with BRCA associated breast cancer who did and did not undergo mastectomy of the contralateral breast.
Retrospective analysis.
12 cancer genetics clinics.
390 women with a family history of stage I or II breast cancer who were carriers of BRCA1 and BRCA2 mutations and initially treated with unilateral or bilateral mastectomy. 181 patients had mastectomy of the contralateral breast. Patients were followed for up to 20 years from diagnosis.
Death from breast cancer.
79 women died of breast cancer in the follow-up period (18 in the bilateral mastectomy group and 61 in the unilateral mastectomy group). The median follow-up time was 14.3 years (range 0.1-20.0 years). At 20 years the survival rate for women who had mastectomy of the contralateral breast was 88% (95% confidence interval 83% to 93%) and for those who did not was 66% (59% to 73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, contralateral mastectomy was associated with a 48% reduction in death from breast cancer (hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P=0.03). In a propensity score adjusted analysis of 79 matched pairs, the association was not significant (0.60, 0.34 to 1.06; P=0.08). Based on these results, we predict that of 100 women treated with contralateral mastectomy, 87 will be alive at 20 years compared with 66 of 100 women treated with unilateral mastectomy.
This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. Given the small number of events in this cohort, further research is required to confirm these findings.
Notes
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Comment In: BMJ. 2014;348:g137924519764
Comment In: BMJ. 2014;348:g186324603573
PubMed ID
24519767 View in PubMed
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Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.

https://arctichealth.org/en/permalink/ahliterature137000
Source
Gynecol Oncol. 2011 May 1;121(2):353-7
Publication Type
Article
Date
May-1-2011
Author
Shiyu Zhang
Robert Royer
Song Li
John R McLaughlin
Barry Rosen
Harvey A Risch
Isabel Fan
Linda Bradley
Patricia A Shaw
Steven A Narod
Author Affiliation
Women's College Research Institute, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, Canada M5G 1N8.
Source
Gynecol Oncol. 2011 May 1;121(2):353-7
Date
May-1-2011
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Aged
Female
Genes, BRCA1
Genes, BRCA2
Germ-Line Mutation
Humans
Middle Aged
Neoplasm Invasiveness
Ontario - epidemiology
Ovarian Neoplasms - epidemiology - genetics - pathology
Prevalence
Young Adult
Abstract
The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.
We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).
Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.
BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.
PubMed ID
21324516 View in PubMed
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42 records – page 1 of 5.