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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/30692095 below:

A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2

. 2019 Feb;28(2):293-302. doi: 10.1158/1055-9965.EPI-18-0584. Epub 2019 Jan 28. A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, Maryland.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, Maryland. KatkiH@mail.nih.gov.

PMID: 30692095
PMCID: PMC7451358
DOI: 10.1158/1055-9965.EPI-18-0584

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A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2

Ana F Best et al. Cancer Epidemiol Biomarkers Prev. 2019 Feb.

. 2019 Feb;28(2):293-302. doi: 10.1158/1055-9965.EPI-18-0584. Epub 2019 Jan 28. Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, Maryland.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, Maryland. KatkiH@mail.nih.gov.

PMID: 30692095
PMCID: PMC7451358
DOI: 10.1158/1055-9965.EPI-18-0584

Item in Clipboard

Abstract

Background: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for BRCA1/2 founder mutation screening in U.S. Ashkenazi-Jewish women.

Methods: BRCA1/2 carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2).

Results: Identifying 90% of BRCA1/2 founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women.

Conclusions: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities.

Impact: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.

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Conflict of interest statement

Conflicts of Interest: None reported.

Figures
Figure 1

A) Fraction of BRCA1/2 founder…

Figure 1

A) Fraction of BRCA1/2 founder mutations identified by percent of Ashkenazi-Jewish women tested.…

Figure 1 A)

Fraction of

BRCA1/2

founder mutations identified by percent of Ashkenazi-Jewish women tested.

Carrier-probability thresholds of 0.56%, 0.78%, 5%, and 10% are indicated vertically.
Table gives values of positive predictive value (PPV) and the complement of the negative predictive value (cNPV) for each threshold.

Fraction of

BRCA1/2

founder mutations identified by percent of subgroup tested, for women under 40 (solid line) and women 40 and older (dashed line).

Carrier-probability thresholds of 0.84%, 1%, 5%, and 10% are indicated vertically for women under 40.
Thresholds of 0.48%, 0.76%, 5%, and 10% are indicated horizontally for women over 40.
Table gives values of positive predictive value (PPV) and the complement of the negative predictive value (cNPV) for each threshold.

Figure 2:

Percent of female BRCA1/2 founder…

Figure 2:

Percent of female BRCA1/2 founder mutation carriers identified among 3 types of family…

Figure 2:

Percent of female BRCA1/2 founder mutation carriers identified among 3 types of family history: (1) high-risk famlies with extensive cancer family-history by National Comprehensive Cancer Network (NCCN) criteria (45% of families). (2) families with some cancer are deemed as “NCCN Ashkenazi-Jewish Family” when NCCN are met when Ashkenazi-Jewish ancestry is also taken into account (24% of families). (3) families with no cancer, deemed ‘low-risk’ if cancer information is known for all 1^st and 2^nd degree relatives, otherwise deemed ‘ambiguous’ if cancer information is missing or a relative died at an early age (31% of families). Example carrier-probability thresholds of 0.56% and 0.78% are indicated vertically.

Figure 3:

Pedigrees for representative volunteer families…

Figure 3:

Pedigrees for representative volunteer families at 0.5% (a), 1% (b), 2.3% (c), 4.9%…

Figure 3:

Pedigrees for representative volunteer families at 0.5% (a), 1% (b), 2.3% (c), 4.9% (d), and 10.6% (e) carrier-probailities. Volunteer is indicated with an arrow, and was chosen to be approximately 35 years old, female, and non-carriers of the BRCA founder mutations. Non-AJ family members are diagonally shaded, male relatives are denoted by blue squares, and cancer-affected, cancer-unaffected, and cancer-unknown female relatives are denoted by red, green, and grey circles respectively. Where available, age at death or interview, or cancer type and age at cancer diagnosis are given below each pedigree member. A) Carrier-probability (CP) is low due to long cancer-free life for both grandmothers and mother, partial AJ heritage (3/4), and lack of early cancer in older sisters. B) Long cancer-free life for mother and maternal grandmother and a lack of early cancer in a 45-year-old sister reduce CP, but lack of information about the paternal grandmother prevents further reduction. C) An older breast cancer in mother balances with moderately long cancer-free life for both grandmothers producing an overall population-average CP. D) Early breast cancer in mother brings the CP to 5%, despite long cancer-free life of the maternal grandmother. E) Ovarian cancer in mother brings CP to 10%, despite long cancer-free life of maternal grandmother.