Robert Royer

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.

BACKGROUND 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.

Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.

BackgroundPALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec.MethodsWe screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls.ResultsWe identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls.ConclusionWe have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.

Screening for Founder Mutations in BRCA1 and BRCA2 in Unselected Jewish Women

PURPOSE There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing. METHODS Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman. Results A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing. CONCLUSION There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.

Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Brazil

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Brazil has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Brazil, we conducted a study of unselected breast cancer patients from Rio de Janeiro, Brazil. We enrolled 402 women with breast cancer from a large public hospital and two private medical clinics in the city. A detailed family history was obtained from each patient and a blood sample was obtained for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. Overall, nine mutations were identified (six in BRCA1 and three in BRCA2) representing 2.3% of the total. The most common mutation, 5382insC in BRCA1, was seen five times and accounted for 56% of all identified mutations. A second mutation, in BRCA2 (6633del5) was seen in two unrelated women. In summary, BRCA1 and BRCA2 mutations are not uncommon in Brazilian women with breast cancer. It appears that a small number of founder mutations may be predominant. Moreover, a small number of founder mutations may be prevalent in Brazil, raising the possibility that a rapid and inexpensive genetic test may be developed to screen for inherited susceptibility to breast cancer in Brazil.

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene—this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas.

The contribution of founder mutations to early-onset breast cancer in French-Canadian women

In an ethnically‐homogeneous population, it is valuable to identify founder mutations in cancer‐predisposing genes. Founder mutations have been found in four breast‐cancer‐predisposing genes in French‐Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French‐Canadian women with early‐onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French‐Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7–28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9–67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4–9.1). One‐half of the women with a mutation had a first‐ or second‐degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French‐Canadian women with early‐onset breast cancer. It is reasonable to offer screening for founder mutations to all French‐Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population‐based screening.

The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30

Germ-line mutations in the TP53 gene are rare, but predispose women to a range of cancer types, including early-onset breast cancer. Breast cancers in women from families with the Li-Fraumeni syndrome often occur before age 30. The prevalence of deleterious TP53 mutations in unselected women with early-onset breast cancer is not precisely known. If mutations were found to be sufficiently common, it might be prudent to offer genetic testing to affected women in this age group. We screened the entire TP53 gene in the germ-line DNA from 95 women of various ethnic groups who were diagnosed with breast cancer before age 30, and who had previously been found to be negative for BRCA1 and BRCA2 mutations. No TP53 mutation was found. This study does not support a policy that TP53 testing should be offered routinely to unselected women with early-onset breast cancer in the absence of a family history of cancer.

Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru

The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation‐positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer.

The R337H mutation in TP53 and breast cancer in Brazil

BackgroundGermline mutations in p53 are associated with the Li-Fraumeni Syndrome which is characterized by childhood cancers, including pediatric adrenal cortical carcinomas and early onset breast cancer. The high incidence of adrenal cortical carcinomas in southern Brazil is mostly attributed to the R337H mutation in TP53. The relatively high population frequency of this mutation in southern Brazil, along with the clustering of early onset breast cancer in Li-Frameni families, suggests this mutation may also be a low-penetrance breast cancer susceptibility polymorphism.MethodsWe undertook this study to evaluate the frequency of the R337H mutation in breast cancer patients from Rio de Janeiro, Brazil. R337H mutation status was determined in 390 unselected breast cases and 324 controls identified from clinics in Rio de Janeiro, Brazil using a PCR-based assay.ResultsTwo of the breast cancer cases (0.5%) and none of the controls carried the mutation. Both cases had an early age at diagnosis (< 40 years old) and a family history of breast and other cancers.ConclusionsThese data suggest genetic screening of young onset breast cancer patients should include testing for the R337H mutation.

Family history, BRCA mutations and breast cancer in Vietnamese women

Ginsburg OM, Dinh NV, To TV, Quang LH, Linh ND, Duong BTH, Royer R, Llacuachaqui M, Tulman A, Vichodez G, Li S, Love RR, Narod SA. Family history, BRCA mutations and breast cancer in Vietnamese women.