Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada.

BACKGROUND: PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient. METHODS: The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario. RESULTS: We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del - major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations. CONCLUSIONS: PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.

Feasibility Study and Clinical Impact of Incorporating Breast Tissue Density in High-Risk Breast Cancer Screening Assessment.

Breast tissue density (BTD) is known to increase the risk of breast cancer but is not routinely used in the risk assessment of the population-based High-Risk Ontario Breast Screening Program (HROBSP). This prospective, IRB-approved study assessed the feasibility and impact of incorporating breast tissue density (BTD) into the risk assessment of women referred to HROBSP who were not genetic mutation carriers. All consecutive women aged 40-69 years who met criteria for HROBSP assessment and referred to Genetics from 1 December 2020 to 31 July 2021 had their lifetime risk calculated with and without BTD using Tyrer-Cuzick model version 8 (IBISv8) to gauge overall impact. McNemar's test was performed to compare eligibility with and without density. 140 women were referred, and 1 was excluded (BRCA gene mutation carrier and automatically eligible). Eight of 139 (5.8%) never had a mammogram, while 17/131 (13%) did not have BTD reported on their mammogram and required radiologist review. Of 131 patients, 22 (16.8%) were clinically impacted by incorporation of BTD: 9/131 (6.9%) became eligible for HROBSP, while 13/131 (9.9%) became ineligible (p = 0.394). It was feasible for the Genetics clinic to incorporate BTD for better risk stratification of eligible women. This did not significantly impact the number of eligible women while optimizing the use of high-risk supplemental MRI screening.

Strategies for recruiting Hispanic women into a prospective cohort study of modifiable risk factors for gestational diabetes mellitus.

BACKGROUND: The purpose of this article was to describe effective strategies for recruitment of Hispanic women into a prospective cohort study of modifiable risk factors for gestational diabetes mellitus (GDM). Although Hispanic women have two to four times the risk of developing GDM compared with non-Hispanic white women, few GDM prevention studies have included Hispanic women. METHODS: The study was conducted in the ambulatory obstetrical practices of Baystate Medical Center located in a socioeconomically and ethnically diverse city in Massachusetts. The study employed a range of strategies to recruit Hispanic women based on a review of the literature as well as prior experience with the study population. RESULTS: Over a period of 32 months, a total of 851 Hispanic prenatal care patients were recruited. Among eligible women, 52.4% agreed to participate. Participants were young (70% <25 years), with low levels of education, and on public health insurance (81.5%); 88% were unmarried. Study design features such as use of bilingual recruiters, a flexible recruitment process, training recruiters to be culturally sensitive, use of culturally tailored materials, prescreening participants, participant compensation, seeking the cooperation of clinic staff, and continuous monitoring of recruitment goals emerged as important issues influencing recruitment. CONCLUSIONS: Findings suggest that investigators can successfully recruit pregnant women from ethnic minority groups of low socioeconomic status into observational studies. The study provides culturally appropriate recruitment strategies useful for practice-based settings recruiting Hispanic research participation.

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma.

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517-29. ©2017 AACR.