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Diane Provencher – One of the best experts on this subject based on the ideXlab platform.

  • a targeted analysis identifies a high frequency of brca1 and brca2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Annemarie Mesmasson, Diane Provencher, Patricia N Tonin
    Abstract:

    The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • A targeted analysis identifies a high frequency of BRCA1 and BRCA2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Diane Provencher, Anne-marie Mes-masson, Patricia N Tonin
    Abstract:

    Background The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. Methods A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. Results A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Conclusions Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • Germline TP53 Mutations in BRCA1 and BRCA2 Mutation-negative French Canadian breast cancer families
    Breast Cancer Research and Treatment, 2008
    Co-Authors: Suzanna L Arcand, Anne-marie Mes-masson, Christine M. Maugard, Parviz Ghadirian, André Robidoux, Chantal Perret, Phil Zhang, Eve Fafard, William D. Foulkes, Diane Provencher
    Abstract:

    About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 Mutations where common Mutations account for about 84% of all Mutations identified in cancer families. Within a series of BRCA1 and BRCA2 Mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) Mutation was identified, which was selected for Mutation analysis in this gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A Mutation was screened in series of 52 BRCA1 and BRCA2 Mutation-negative cancer families, and a Mutation-positive family was identified. However, pedigree inspection and expansion of Mutation-positive families with the same Mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, Mutation analysis was performed in the remaining BRCA1 and BRCA2 Mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) Mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like (LFL) syndrome. Neither of the TP53 Mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 Mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 Mutation-negative breast and/or ovarian cancer families of French Canadian descent.

Patricia N Tonin – One of the best experts on this subject based on the ideXlab platform.

  • a targeted analysis identifies a high frequency of brca1 and brca2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Annemarie Mesmasson, Diane Provencher, Patricia N Tonin
    Abstract:

    The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • A targeted analysis identifies a high frequency of BRCA1 and BRCA2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Diane Provencher, Anne-marie Mes-masson, Patricia N Tonin
    Abstract:

    Background The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. Methods A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. Results A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Conclusions Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

Suzanna L Arcand – One of the best experts on this subject based on the ideXlab platform.

  • a targeted analysis identifies a high frequency of brca1 and brca2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Annemarie Mesmasson, Diane Provencher, Patricia N Tonin
    Abstract:

    The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • A targeted analysis identifies a high frequency of BRCA1 and BRCA2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Diane Provencher, Anne-marie Mes-masson, Patricia N Tonin
    Abstract:

    Background The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. Methods A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. Results A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Conclusions Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • Germline TP53 Mutations in BRCA1 and BRCA2 Mutation-negative French Canadian breast cancer families
    Breast Cancer Research and Treatment, 2008
    Co-Authors: Suzanna L Arcand, Anne-marie Mes-masson, Christine M. Maugard, Parviz Ghadirian, André Robidoux, Chantal Perret, Phil Zhang, Eve Fafard, William D. Foulkes, Diane Provencher
    Abstract:

    About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 Mutations where common Mutations account for about 84% of all Mutations identified in cancer families. Within a series of BRCA1 and BRCA2 Mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) Mutation was identified, which was selected for Mutation analysis in this gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A Mutation was screened in series of 52 BRCA1 and BRCA2 Mutation-negative cancer families, and a Mutation-positive family was identified. However, pedigree inspection and expansion of Mutation-positive families with the same Mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, Mutation analysis was performed in the remaining BRCA1 and BRCA2 Mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) Mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like (LFL) syndrome. Neither of the TP53 Mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 Mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 Mutation-negative breast and/or ovarian cancer families of French Canadian descent.

Lawrence A Loeb – One of the best experts on this subject based on the ideXlab platform.

  • the Mutation rate and cancer
    Genetics, 1998
    Co-Authors: Aimee L Jackson, Lawrence A Loeb
    Abstract:

    The stability of the human genome requires that Mutations in the germ line be exceptionally rare events. While most Mutations are neutral or have deleterious effects, a limited number of Mutations are required for adaptation to environmental changes. Drake has provided evidence that DNA-based microbes have evolved a mechanism to yield a common spontaneous Mutation rate of ~0.003 Mutations per genome per replication (Drake 1991). In contrast, Mutation rates of RNA viruses are much larger (Holland et al. 1982) and can approach the maximum tolerable deleterious Mutation rate of one per genome (Eigen and Schuster 1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous Mutation rates of approximately one per genome while most have Mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline Mutation rates among microbial species need not necessarily mean constancy of the somatic Mutation rates. Furthermore, there need not be a constant rate for somatic Mutations during development. In this review, we consider Mutations in cancer, a pathology in which there appears to be an increase in the rate of somatic Mutations throughout the genome. Moreover, within the eukaryotic genome, as in microbes, there are “hot-spots” that exhibit unusually high Mutation frequencies. It seems conceivable to us that many tumors contain thousands of changes in DNA sequence. The major question is: how do these Mutations arise, and how many are rate-limiting for tumor progression?

Moria H Belanger – One of the best experts on this subject based on the ideXlab platform.

  • a targeted analysis identifies a high frequency of brca1 and brca2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Annemarie Mesmasson, Diane Provencher, Patricia N Tonin
    Abstract:

    The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.

  • A targeted analysis identifies a high frequency of BRCA1 and BRCA2 Mutation carriers in women with ovarian cancer from a founder population
    Journal of Ovarian Research, 2015
    Co-Authors: Moria H Belanger, Lena Dolman, Suzanna L Arcand, Zhen Shen, George Chong, Diane Provencher, Anne-marie Mes-masson, Patricia N Tonin
    Abstract:

    Background The frequency of BRCA1 and BRCA2 Mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 Mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 Mutations, a defined subgroup of 116 cases were investigated for all Mutations previously reported in this population. Methods A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K Mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific Mutations that have ever been reported in French Canadians, which included the six Mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. Results A targeted analysis of six Mutations identified 34/439 (7.7%) Mutation carriers and at least two Mutation carriers for each Mutation screened were found. The BRCA1:C4446T Mutation was the most frequently identified variant (15/34, 44.1%) among Mutation-positive cases. The expanded Mutation screen that also included 13 additional variants identified 19/116 (16.4%) Mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among Mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with Mutations identified in 19.2% (n = 14) serous cases. Conclusions Our results reaffirm that specific BRCA1 and BRCA2 Mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of Mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.