Predictors of genetic risk recall among the participants of a randomized controlled precision prevention trial against melanoma.

PURPOSE: Inherited variation in MC1R imparts low to moderate risk of melanoma. Research on genetic risk recall, factors predicting recall, and whether recall influences adoption of preventive behaviors is limited. METHODS: Participants (n = 447) enrolled in a melanoma precision prevention trial were provided with MC1R risk information (average or higher) and after 6 and 12 months, were asked to recall their genetic risk. Predictors of recall were identified using backward stepwise selection. Intervention effects were reassessed after stratifying by recall. RESULTS: Participants at higher risk were 2 to 3 times more likely to misremember or not recall than participants with average risk. Misremembering was almost exclusively observed among participants at higher risk. Among the participants with average risk, lower health numeracy and not completing the telephone follow-up were associated with not recalling or misremembering. Among the participants at higher risk, lower education was associated with not recalling and lower perceived comparative chance of developing melanoma was associated with misremembering. In general, participants at higher risk who correctly recalled had modestly stronger intervention effects on sun protection behaviors than those who misremembered or did not recall. CONCLUSION: Future studies should examine different strategies to increase genetic risk recall, which may result in improved behavioral outcomes, especially among participants with lower education and health numeracy.

Factors that influence the management recommendations breast surgeons provide to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes.

Pathogenic variants in moderate penetrance breast cancer susceptibility genes, such as ATM and CHEK2, confer a two- to five-fold increased lifetime risk for breast cancer. The National Comprehensive Cancer Network has guidelines for breast surgeons to utilize when counseling women with pathogenic variants in these genes; however, previous studies indicate that other factors impact breast surgeons' recommendations to patients. This study investigated factors influencing management recommendations presented by breast surgeons to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Focus groups and interviews were conducted with breast surgeons practicing in Ohio, Kentucky, and Indiana. A total of 15 breast surgeons from eight different hospitals participated in five focus groups and three individual interviews. Participants discussed factors they consider when making management recommendations for risk reduction in women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Participants provided risk management recommendations for given scenarios. Patient motivation/opinion, family history, patient current health status, patient personal preference, and patient anxiety level were among the most common factors mentioned. It appeared that how these factors are valued and applied in practice varies. There was no consensus among breast surgeons on which risk-reducing management options they would recommend in each scenario. There are many factors breast surgeons take into consideration when making recommendations for this patient population. This information could inform future research on decision making around treatment for individuals with pathogenic variants in moderate penetrance breast cancer susceptibility genes.

Toward a better understanding of the experience of patients with moderate penetrance breast cancer gene pathogenic/likely pathogenic variants: A focus on ATM and CHEK2.

This study explored the experiences of patients with pathogenic or likely pathogenic variants in the moderate penetrance breast cancer genes, ATM and CHEK2. There were 139 eligible female patients who received genetic counseling at the Massachusetts General Hospital Center for Cancer Risk Assessment (MGH CCRA) from 2014 to 2018. They were sent surveys assessing their understanding of the clinical significance of their genetic test results, adherence to medical management recommendations, dissemination of genetic test results to relatives, and informational resource needs. In total, 66 surveys were returned with a response rate of 47.5%. Most participants reported understanding the clinical implications of their genetic test results and adhering to medical management recommendations. Although 20.3% found it upsetting, nearly all participants shared their genetic test results with relatives. When asked about resource needs, 54.5% reported seeking out additional resources. Our ATM/CHEK2 sample appears to have a good understanding of the personal and familial implications of their genetic test results but may benefit from additional resources. It is unclear whether similar results would be found in patients who do not receive genetic counseling from a board-certified genetic counselor, and this should be examined. This study is one of the first to assess the experiences and needs of the moderate risk population.

Cancer Genetic Counseling and Testing: Perspectives of Epithelial Ovarian Cancer Patients and Gynecologic Oncology Healthcare Providers.

Multi-gene panel testing has expanded the genetic information available to cancer patients. The objective was to assess provider behaviors and attitudes and patient knowledge and attitudes towards genetic counseling and testing. An online survey was distributed to Society of Gynecologic Oncology members and a written questionnaire was administered to patients diagnosed with epithelial ovarian cancer at a tertiary care referral center. Most of the 233 (18% response rate) provider respondents were gynecologic oncologists. Access to a genetic counselor was reported by 87% of providers and 55% deferred all testing to genetic counselors. Of 53 ovarian cancer patient respondents, two-thirds had previously seen a genetic counselor or undergone testing. Patients' attitudes about genetic counseling and/or testing were favorable with respect to themselves (70-81%) and their family members (94%). Less than 25% of patients indicated worrying about health care discrimination, lack of privacy, or high cost. Seventy-seven percent of patients demonstrated a desire to obtain genetic information even if the results were not currently actionable, and 20% of providers stated they test for only those genes with guideline-supported actionable results. Provider practice differences were identified in screening and prevention strategies for patients with deleterious non-BRCA mutations and variants of uncertain significance. The variation in clinical interpretation of results associated with poorly defined cancer risks signals a need for more comprehensive training and guidelines to ensure access to evidence-based care.

Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey.

The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03 % in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer.

Impact of High-to-Moderate Penetrance Genes on Genetic Testing: Looking over Breast Cancer.

Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2, many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of BRCA1/2 with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ATM (n = 4), CHEK2 (n = 5), PALB2 (n = 2), RAD51C (n = 1), and RAD51D (n = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of CHEK2 variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond BRCA1/2 identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing BRCA1/2 alone.

Predictors of correct recall of genetic risk information among Hispanic individuals in Florida and Puerto Rico.

OBJECTIVE: To identify predictors of genetic risk recall and examine whether recall influences adoption of skin cancer preventive behaviors among Hispanic individuals. METHODS: Hispanic participants randomized to intervention arms (n = 463) of a precision prevention trial were provided MC1R risk information (average, higher) and asked to recall their risk after 3 and 9 months. Predictors of recall (correct versus did not recall/misremembered) were determined by backwards stepwise logistic regression. Intervention effects on preventive behaviors were estimated within strata of 3-month recall. RESULTS: Age inversely predicted correct recall in both risk groups (average: OR3-months(3)= 0.97, 95%CI:0.94-1.01, OR9-months(9)= 0.96, 95%CI:0.93-0.99; higher: OR3 = 0.98, 95%CI:0.95-1.01, OR9 = 0.98, 95%CI:0.95-1.00). Education positively predicted recall among participants at average risk (OR3 =1.64, 95%CI:1.06-2.63, OR9 =1.73, 95%CI:1.12-2.81). Darker untanned skin color inversely predicted recall among participants at higher risk (OR3 =0.68, 95%CI:0.45-0.99, OR9 =0.74, 95%CI:0.50-1.09). Intervention effects for routine sunscreen use and undergoing a clinical skin exam were stronger among participants at higher risk who correctly recalled at 3 months than those who did not recall/misremembered. CONCLUSIONS: Younger age, higher education, and lighter untanned skin color predicted correct recall. Better recall may improve skin cancer prevention outcomes. PRACTICE IMPLICATIONS: Additional strategies are needed to boost recall among Hispanic individuals who are older, less educated, and darker-skinned.

Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry.

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.

Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS. METHODS: A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing. RESULTS: We identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes: [MLH1-BRCA2-NBN], [MLH1-BRCA1], [MSH2-ATM], [MSH6-NF1], and [MLH1-FANCA]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [MLH1-BRCA2-NBN] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome. CONCLUSIONS: Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

The impact of the number of tests presented and a provider recommendation on decisions about genetic testing for cancer risk.

OBJECTIVE: To determine how the method of presenting testing options and a provider recommendation can influence a decision about genetic testing for inherited cancer predispositions. METHODS: An online hypothetical vignette study was completed by 454 healthy volunteers. Participants were randomized to receive one of two survey versions which differed by genetic testing choice presentation. One group was shown three options simultaneously (no test, 5-gene or 15-gene), and a second group received the 15-gene option after choosing between the no test and 5-gene options. A preference-based provider recommendation was also incorporated. We examined the effect of these interventions on test selection. RESULTS: Participants in the simultaneous group were more likely to choose a genetic test than those in the sequential group (OR: 2.35, p=0.003). This effect was no longer observed when individuals who had selected no-test in the sequential group were told about the 15-gene test (OR: 1.03 p=0.932). Incorporating a provider recommendation into the hypothetical scenario led to more preference-consistent choices (χ2 = 8.53, p < 0.0035,). CONCLUSIONS: A larger menu of testing choices led to higher testing uptake. A preference-based clinician recommendation resulted in more preference-consistent choices. PRACTICE IMPLICATIONS: The structuring of testing options and preference-sensitive recommendations appear to facilitate informed testing decisions.