[Show abstract][Hide abstract] ABSTRACT: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.
TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.
Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.
In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.
BMC Medical Genetics 12/2015; 16(1):24. DOI:10.1186/s12881-015-0169-y · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To measure weight gain among unaffected women with a BRCA1 or BRCA2 mutation after undergoing an oophorectomy.
We compared the bodyweight of women with (n = 405) and without an oophorectomy (n = 741) at baseline as well as the rate of weight change prior to and following surgery among 1454 BRCA mutation carriers who had an oophorectomy.
There was a small and non-significant difference in bodyweight between BRCA mutation carriers who had an oophorectomy compared with those women who did not (151.5 vs 149.1 pounds; p = 0.26). There was an increase in bodyweight with increasing age, but this relationship did not differ prior to and following surgery (p comparing the slope parameters = 0.78).
Oophorectomy is not associated with significant weight gain in high-risk women.
Women s Health 08/2015; 11(4):1-7. DOI:10.2217/WHE.15.4
[Show abstract][Hide abstract] ABSTRACT: Over the past decade, chromatin remodelling disorders have emerged as one of the most important causes of both abnormal development and cancer. Although much has been written about one or another of the complexes, no recent concise summary of the chromatin remodelling families as a whole is available. In this short review, we introduce the family members, briefly summarize their role in developmental abnormalities and neoplasia and outline the different ways in which these families remodel chromatin.
This article is protected by copyright. All rights reserved.
The Journal of Pathology 07/2015; DOI:10.1002/path.4585 · 7.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA-associated breast cancer.
To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation.
Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy.
In all analyses, the primary end point was death due to breast cancer.
Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer-specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor-positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor-negative breast cancer.
Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor-negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Advances in sequencing technology have made multigene testing, or "panel testing," a practical option when looking for genetic variants that may be associated with a risk of breast cancer. In June 2013, the U.S. Supreme Court(1) invalidated specific claims made by Myriad Genetics with respect to the patenting of the genomic DNA sequence of BRCA1 and BRCA2. Other companies immediately began to offer panel tests for breast cancer genes that included BRCA1 and BRCA2. The subsequent flourishing of gene-panel testing services (Table 1, and Table S1 in the Supplementary Appendix, available with the full text of this article at . . .
New England Journal of Medicine 05/2015; 372(23). DOI:10.1056/NEJMsr1501341 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.
Breast Cancer Research and Treatment 05/2015; 151(2). DOI:10.1007/s10549-015-3393-4 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Recent studies have demonstrated somatic mutations in DICER1 in approximately 60% of ovarian Sertoli-Leydig cell tumors. Furthermore, patients with germline mutations in DICER1 are predisposed to developing a range of rare neoplasms including ovarian sex cord-stromal tumors most of which have been classified as Sertoli-Leydig cell tumor. However, the histologic features of these tumors have not been reported in detail. We describe the morphologic and immunophenotypic findings of 4 sex cord-stromal tumors arising in patients with proven or likely germline DICER1 mutations including 3 individuals from 1 family. Three tumors showed similar appearances characterized by marked architectural and cytologic heterogeneity including sertoliform, juvenile granulosa cell tumor-like, and unclassifiable elements. The remaining case mainly showed heterologous mucinous epithelial and neuroendocrine differentiation with only a minor intermediate-grade Sertoli cell component. This tumor and one of the 3 former cases arose in related patients with identical germline DICER1 mutations indicating that additional factors influence tumor morphology. All tumors were positive for steroidogenic factor-1 and FOXL2 on immunohistochemical analysis, whereas there was more variable expression of inhibin, calretinin, CD56, CD99, and hormone receptors. The present small series suggests that some ovarian Sertoli-Leydig cell tumor associated with germline DICER1 mutations may show distinctive histologic features in particular admixed Sertoli cell and juvenile granulosa cell tumor-like features. Larger studies are required to establish whether heterologous elements are also a more common feature of these tumors.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2015; 34(3):266-274. DOI:10.1097/PGP.0000000000000150 · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: •Prophylactic oophorectomy can prevent small cell carcinoma of the ovary, hypercalcemic type in carriers of germline SMARCA4 mutations.•Unaffected SMARCA4 mutation carriers who desire children may be best served by oocyte cryopreservation prior to prophylactic oophorectomy.
[Show abstract][Hide abstract] ABSTRACT: Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.
[Show abstract][Hide abstract] ABSTRACT: Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
We genotyped 22214 (11421 affected, 10793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched for affected or unaffected individuals.
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers than the rest of clade T, (Hazard Ratio (HR) = 0.55 (95% Confidence Interval (CI) 0.34-0.88, p-value = 0.01). Compared with the most frequent haplogroup in the general population i.e. H and T clade, the T1a1 haplogroup has an HR = 0.62 (95% CI = 0.40-0.95, p-value = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
This study illustrates how original approaches like the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Breast cancer research: BCR 04/2015; 17(1):61. DOI:10.1186/s13058-015-0567-2 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies.
Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk.
The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases.
Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
Current Oncology 04/2015; 22(2):113-21. DOI:10.3747/co.22.2300 · 1.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare the risks of radiation in screening strategies using chest radiographs and CT to detect a rare cancer in a genetically predisposed population against the risks of undetected disease.
A decision analytic model of diagnostic imaging screening strategies was built to predict outcomes and cumulative radiation doses for children with DICER1 mutations screened for pleuropulmonary blastoma. Screening strategies compared were chest radiographs followed by chest CT for a positive radiographic result and CT alone. Screening frequencies ranged from once in 3 years to once every 3 months. BEIR VII (model VII proposed by the Committee on the Biological Effects of Ionizing Radiation) risk tables were used to predict excess cancer mortality for each strategy, and the corresponding loss of life expectancy was calculated using Surveillance Epidemiologic and End Results (SEER) statistics. Loss of life expectancy owing to undetected progressive pleuropulmonary blastoma was estimated on the basis of data from the International Pleuropulmonary Blastoma Registry. Sensitivity analysis was performed for all model parameters.
Loss of life expectancy owing to undetected disease in an unscreened population exceeded that owing to radiation-induced cancer for all screening scenarios investigated. Increases in imaging frequency decreased loss of life expectancy for the combined (chest radiographs and CT) screening strategy but increased that for the CT-only strategy. This was because loss of life expectancy for combined screening is dominated by undetected disease, whereas loss of life expectancy for CT screening is dominated by radiation-induced cancers.
Even for a rare disease such as pleuropulmonary blastoma, radiographic screening of infants and young children with cancer-predisposing mutations may result in improved life expectancy compared with the unscreened population. The benefit of screening will be greater for diseases with a higher screening yield.
American Journal of Roentgenology 04/2015; 204(4):W475-W482. DOI:10.2214/AJR.14.12802 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Inherited mutations in DNA mismatch
repair genes predispose to different cancer syndromes
depending on whether they are mono-allelic or bi-allelic.
This supports a causal relationship between expression
level in the germline and phenotype variation. As a
model to study this relationship, our study aimed to
define the pathogenic characteristics of a recurrent
homozygous coding variant in PMS2 displaying an
attenuated phenotype identified by clinical genetic
testing in seven Inuit families from Northern Quebec.
Methods Pathogenic characteristics of the PMS2
mutation NM_000535.5:c.2002A>G were studied using
genotype–phenotype correlation, single-molecule
expression detection and single genome microsatellite
Results This PMS2 mutation generates a de novo
splice site that competes with the authentic site. In
homozygotes, expression of the full-length protein is
reduced to a level barely detectable by conventional
diagnostics. Median age at primary cancer diagnosis is
22 years among 13 NM_000535.5:c.2002A>G
homozygotes, versus 8 years in individuals carrying biallelic
truncating mutations. Residual expression of fulllength
PMS2 transcript was detected in normal tissues
from homozygotes with cancers in their 20s.
Conclusions Our genotype–phenotype study of
c.2002A>G illustrates that an extremely low level of
PMS2 expression likely delays cancer onset, a feature
that could be exploited in cancer preventive intervention.