Multi-gene Hereditary Cancer Panel Research Articles

Family communication of cancer genetic test results in an ethnically diverse population: a qualitative exploration of more than 200 patients.

Previous research on family communication of cancer genetic test results has primarily focused on non-Hispanic White patients with high-risk pathogenic variants (PV). There are limited data on patient communication of moderate-risk PVs, variants of uncertain significance (VUS), and negative results. This qualitative study examined communication of positive, negative, and VUS hereditary cancer multi-gene panel (MGP) results in an ethnically and socioeconomically diverse population. As part of a multicenter, prospective cohort study of 2000 patients who underwent MGP testing at three hospitals in California, USA, free-text written survey responses to the question: "Feel free to share any thoughts or experiences with discussing genetic test results with others" were collected from participant questionnaires administered at 3 and 12-months post results disclosure. Content and thematic analyses were performed using a theory-driven analysis, Theory of Planned Behavior (TPB), on 256 responses from 214 respondents. Respondents with high perceived utility of sharing genetic test results often reported positive attitudes towards sharing test results and direct encouragement for genetic testing of others. Respondents with high self-efficacy in the sharing process were likely to report high perceived utility of sharing, whereas patients with low self-efficacy more often had VUS results and were more likely to report uncertainty about sharing. Consistent with TPB, our findings suggest that clinician reinforcement of the utility of genetic testing may increase intent for patients to communicate genetic information. Our findings suggest that clinicians should focus on strategies to improve patient understanding of VUS results.

Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis.

Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.

Germline Genetic Testing Among Women ≤ 45Years of Age with Ductal Carcinoma In Situ Versus Invasive Breast Cancer in a Large Integrated Health Care System.

We compared the results of hereditary cancer multigene panel testing among patients ≤ 45years of age diagnosed with ductal carcinoma in situ (DCIS) versus invasive breast cancer (IBC) in a large integrated health care system. A retrospective cohort study of hereditary cancer gene testing among women ≤ 45years of age diagnosed with DCIS or IBC at Kaiser Permanente Northern California between September 2019 and August 2020 was performed. During the study period, institutional guidelines recommended the above population be referred to genetic counselors for pretesting counseling and testing. A total of 61 DCIS and 485 IBC patients were identified. Genetic counselors met with 95% of both groups, and 86.4% of DCIS patients and 93.9% of IBC patients (p = 0.0339) underwent gene testing. Testing differed by race/ethnicity (p = 0.0372). Among those tested, 11.76% (n = 6) of DCIS patients and 16.71% (n = 72) of IBC patients had a pathogenic variant (PV) or likely pathogenic variant (LPV) based on the 36-gene panel (p = 0.3650). Similar trends were seen in 13 breast cancer (BC)-related genes (p = 0.0553). Family history of cancer was significantly associated with both BC-related and non-BC-related PVs in IBC, but not DCIS. In our study, 95% of patients were seen by a genetic counselor when age was used as an eligibility criterion for referral. While larger studies are needed to further compare the prevalence of PVs/LPVs among DCIS and IBC patients, our data suggest that even in younger patients, the prevalence of PVs/LPVs in BC-related genes is lower in DCIS patients.

Clinical implications of conflicting variant interpretations in the cancer genetics clinic

PurposeThe aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants. MethodsResults from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict. ResultsFifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were used for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification. ConclusionOur findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.

Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.

PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.

Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer.

Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.

Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer.

We aimed to determine whether monoallelic MUTYH pathogenic and likely pathogenic variants (PVs) are associated with colorectal, breast, and endometrial cancer. Cases were individuals with colorectal, female breast, or endometrial cancer who reported European ancestry alone and underwent a multi-gene hereditary cancer panel at a large reference laboratory. Controls were individuals of European (non-Finnish) descent from GnomAD with cancer cohorts removed. We performed a Fisher's exact test to generate odds ratios (ORs) with 95% confidence intervals (CI). Prevalence of single MUTYH PVs in cancer cohorts versus controls, respectively, was: colorectal cancer, 2.1% vs. 1.8% (OR 1.2, 95% CI 0.99-1.5, p = 0.064); breast cancer 1.9% vs. 1.7% (OR 1.1, 95% CI 0.96-1.3, p = 0.15); and endometrial cancer, 1.7% vs. 1.7% (OR 0.98; 95% CI 0.70-1.3, p = 0.94). Using the largest colorectal and endometrial cancer cohorts and one of the largest breast cancer cohorts from a single case-control study, we did not observe a significant difference in the prevalence of monoallelic MUTYH PVs in these cohorts compared to controls. Additionally, frequencies among cancer cohorts were consistent with the published MUTYH carrier frequency of 1-2%. These findings suggest there is no association between colorectal, endometrial, or breast cancer and MUTYH heterozygosity in individuals of European ancestry.

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian, pancreatic, and prostate cancer

PurposeTo address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone. MethodsAmong 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model. ResultsOnly 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (pTime < 0.001; pTime2 < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty. ConclusionThis mainstreaming model may offer a feasible approach for extending access to germline genetic information.

Closing the gap: Trends in inconclusive rates on hereditary cancer testing across racial/ethnic groups.

10525 Background: Several groups have described disparities in genetic test results for inherited breast cancer predisposition, with a disproportionate number of variants of unknown significance (VUS) reported in non-Caucasian individuals. These disparities are due in part to the underrepresentation of non-Caucasians in reference databases and clinical genetic testing cohorts. Over the past few years, diversification efforts have been made however, little data exists on how ethnicity- and gene-specific VUS rates have changed over time and whether such disparities have improved or worsened. Methods: We retrospectively reviewed demographic information and test results for individuals who underwent hereditary cancer multigene panel testing between March 2012 and September 2020 at a single laboratory. Individuals who self-reported as African American, Asian, Caucasian, or Hispanic on the test requisition form and whose testing included ATM, BRCA1, BRCA2, CHEK2 and PALB2 (five commonly tested breast cancer predisposition genes with management guidelines) were included in the study (n = 284,130). The frequency of germline variants of unknown significance (VUS) in the five genes was assessed in September 2015 and September 2020. Results: Amongst patients tested between March 2012 and September 2015, 82.8% of the study cohort self-reported as Caucasian and 17.2% were not Caucasian (6.5% African American, 6.0% Hispanic, and 4.6% Asian). The proportion of non-Caucasian individuals in the study cohort increased slightly by September 2020 to 22.8% (77.2% Caucasian, 9.2% African American, 8.4% Hispanic, and 5.3% Asian). Consistent with previous reports, Caucasians had the lowest VUS rate overall in both 2015 and 2020. This was also true at the individual gene level, with the exception of CHEK2. Over time, we observed a relative decrease in VUS rates across all ethnicities. Between 2015 and 2020, the overall VUS rate for the five included genes in non-Caucasian individuals was reduced by 32.0% in non-Caucasians compared to 23.6% in Caucasians. The absolute difference in VUS rate between non-Caucasians and Caucasians decreased from 7.9% in 2015 to 4.5% in 2020. Conclusions: While VUS rates for commonly tested breast cancer predisposition genes remain higher in non-Caucasians relative to Caucasians, our results demonstrate that this gap has been reduced over a five-year time period. These findings may be indicative of efforts by clinicians and laboratories to reduce these disparities. Further studies are necessary to improve the clinical utility of genetic testing in under-represented populations.[Table: see text]

Racial and Ethnic Differences in Multigene Hereditary Cancer Panel Test Results for Women With Breast Cancer.

To evaluate the racial and ethnic differences in prevalence of germline pathogenic variants (PVs) and the effect of race and ethnicity on breast cancer (BC) risk among carriers, results of multigene testing of 77 900 women with BC (non-Hispanic White [NHW] = 57 003; Ashkenazi-Jewish = 4798; Black = 6722; Hispanic = 5194; and Asian = 4183) were analyzed, and the frequency of PVs in each gene were compared between BC patients (cases) and race- and ethnicity-matched gnomAD reference controls. Compared with NHWs, BRCA1 PVs were enriched in Ashkenazi-Jews and Hispanics, whereas CHEK2 PVs were statistically significantly lower in Blacks, Hispanics, and Asians (all 2-sided P < .05). In case-control studies, BARD1 PVs were associated with high risks (odds ratio > 4.00) of BC in Blacks, Hispanics, and Asians; ATM PVs were associated with increased risk of BC among all races and ethnicities except Asians, whereas CHEK2 and BRIP1 PVs were associated with increased risk of BC among NHWs and Hispanics only. These findings suggest a need for personalized management of BC risk in PV carriers based on race and ethnicity.

Association of a Polygenic Risk Score With Breast Cancer Among Women Carriers of High- and Moderate-Risk Breast Cancer Genes

To date, few studies have examined the extent to which polygenic single-nucleotide variation (SNV) (formerly single-nucleotide polymorphism) scores modify risk for carriers of pathogenic variants (PVs) in breast cancer susceptibility genes. In previous reports, polygenic risk modification was reduced for BRCA1 and BRCA2 PV carriers compared with noncarriers, but limited information is available for carriers of CHEK2, ATM, or PALB2 PVs. To examine an 86-SNV polygenic risk score (PRS) for BRCA1, BRCA2, CHEK2, ATM, and PALB2 PV carriers. A retrospective case-control study using data on 150 962 women tested with a multigene hereditary cancer panel between July 19, 2016, and January 11, 2019, was conducted in a commercial testing laboratory. Participants included women of European ancestry between the ages of 18 and 84 years. Multivariable logistic regression was used to examine the association of the 86-SNV score with invasive breast cancer after adjusting for age, ancestry, and personal and/or family cancer history. Effect sizes, expressed as standardized odds ratios (ORs) with 95% CIs, were assessed for carriers of PVs in each gene as well as for noncarriers. The median age at hereditary cancer testing of the population was 48 years (range, 18-84 years); there were 141 160 noncarriers in addition to carriers of BRCA1 (n = 2249), BRCA2 (n = 2638), CHEK2 (n = 2564), ATM (n = 1445), and PALB2 (n = 906) PVs included in the analysis. The 86-SNV score was associated with breast cancer risk in each of the carrier populations (P < 1 × 10-4). Stratification was more pronounced for noncarriers (OR, 1.47; 95% CI, 1.45-1.49) and CHEK2 PV carriers (OR, 1.49; 95% CI, 1.36-1.64) than for carriers of BRCA1 (OR, 1.20; 95% CI, 1.10-1.32) or BRCA2 (OR, 1.23; 95% CI, 1.12-1.34) PVs. Odds ratios for ATM (OR, 1.37; 95% CI, 1.21-1.55) and PALB2 (OR, 1.34; 95% CI, 1.16-1.55) PV carrier populations were intermediate between those for BRCA1/2 and CHEK2 noncarriers. In this study, the 86-SNV score was associated with modified risk for carriers of BRCA1, BRCA2, CHEK2, ATM, and PALB2 PVs. This finding supports previous reports of reduced PRS stratification for BRCA1 and BRCA2 PV carriers compared with noncarriers. Modification of risk in CHEK2 carriers associated with the 86-SNV score appeared to be similar to that observed in women without a PV. Larger studies are needed to provide more refined estimates of polygenic modification of risk for women with PVs in other moderate-penetrance genes.

The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort.

BackgroundThe germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined.MethodsA total of 54 555 invasive breast cancer patients with 56 480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls.ResultsMutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1, and PALB2 mutations were enriched in ER- and HER2- tumors; RAD51C and RAD51D mutations were enriched in ER- tumors only; TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio > 2.00) or strong (odds ratio > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of at least 20.0% for breast cancer.ConclusionsGermline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing.

Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort

PurposeGenetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants. MethodsWe analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions. ResultsTwenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign. ConclusionThe evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.

Ancestry-specific hereditary cancer panel yields: Moving toward more personalized risk assessment.

Healthcare disparities in genomic medicine are well described. Despite some improvements, we continue to see fewer individuals of African American, Asian, and Hispanic ancestry undergo genetic counseling and testing compared to those of European ancestry. It is well established that variant of uncertain significance (VUS) rates are higher among non-European ancestral groups undergoing multi-gene hereditary cancer panel testing. However, pathogenic variant (PV) yields, and genomic data in general, are often reported in aggregate and derived from cohorts largely comprised of individuals of European ancestry. We performed a retrospective review of clinical and ancestral data for individuals undergoing multi-gene hereditary cancer panel testing to determine ancestry-specific PV and VUS rates. An ancestry other than European was reported in 29,042/104,851 (27.7%) of individuals. Compared to Europeans (9.4%), individuals of Middle Eastern ancestry were more likely to test positive for one or more pathogenic variants (12.1%, p=.0025), while African Americans were less likely (7.9%, p<.0001). Asian and Middle Eastern individuals were most likely (34.8% and 33.2%, respectively) to receive a report with an overall classification of VUS, while individuals of Ashkenazi Jewish and European ancestry were least likely (17.1% and 20.4%, respectively). These data suggest that in addition to higher VUS rates, there may be ancestry-specific PV yields. Providing aggregate data derived from cohorts saturated with European individuals does not adequately reflect genetic testing outcomes in minority groups, and interrogation of ancestry-specific data is a step toward a more personalized risk assessment.

1012P - A multi-center integrative study on cancer predisposition genes in Chinese patients with epithelial ovarian carcinoma

BackgroundThe prevalence of BRCA1 and BRCA2 mutations varies among individual racial and ethnic groups. While, molecular epidemiological data on Chinese ovarian cancer patients is still insufficient. MethodsHere, we performed a multicenter study to investigate the clinical and molecular characteristics of 1,059 ovarian cancer patients. A hereditary cancer multigene panel including all NCCN recommended homologues recombination repair genes was performed. ResultsTotally, 1,059 patients with ovarian (n=982, 92.7%), fallopian tube (n=63, 5.9%) and peritoneal (n=14, 1.3%) cancer were recruited from 18 medical centers in China. 314 of 1,059 patients carried deleterious germline aberration in HRR genes including BRCA1 (19.1%), BRCA2 (6.5%) and other HRR genes (4.1%). Another 15 patients carried abnormality in MMR pathway as well as genes of other familial cancer syndrome like MUTYH, STK11, TP53. Histologically, BRCA1/2 mutations, in our study, were enriched not only in HGSC, but also in HGSC (P<0.001 for BRCA1, P=0.05 for BRCA2), which was seldomly investigated. Patients with germline BRCA1 mutations associated with early-onset (age≤50 years, P<0.001), higher chances of breast cancer (P<0.001), family history of HBOC (P<0.001) and relapse after initial treatment (P=0.068). Recurrent patients harbored more deleterious mutations than primary patients although the differences reached no significance in patients with HGSC subtype (P=0.056), suggesting a selection bias. Moreover, it is of our greatest interest that sensitivity to platinum-based therapy was largely depending on BRCA2 status (P=0.023 for all ovarian cancer, P=0.035 for HGSC). While, no significant association was found in BRCA1 mutated group (P=0.3). ConclusionsTo date, it is the largest study on predisposition genes in ovarian carcinoma in Chinese population. Our study disclosed a more complexed spectrum as well as higher rate of germline aberrations compared with previously published data. Etiologically, our data revealed a putative contribution of mutated BRCA1 gene to the onset of ovarian cancer with serous phenotype. Clinically, BRCA2 and other HRR and MMR genes may be used as useful predictive tools for Platinum sensitivity. Legal entity responsible for the studyBGI Genomics. FundingBGI genomics. DisclosureC. Zhu: Full / Part-time employment: BGI genomics. D. Shao: Full / Part-time employment: BGI genomics. All other authors have declared no conflicts of interest.

Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls

BackgroundGenes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer.MethodsA retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (ORAdj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes.ResultsSignificant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (ORCrude) or by ORAdj, respectively. However, there was no significant difference between ORCrude and ORAdj for these two genes. The significant association of PVs in BRIP1 by ORCrude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by ORAdj (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04).ConclusionThe lack of association of PVs in BRIP1 with OC by ORAdj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting ORAdj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.

Abstract P5-10-02: Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among Hispanic women in the United States. For women of European ancestry, genome-wide association studies (GWAS) have identified common variants, primarily single-nucleotide polymorphisms (SNPs), that individually confer modest risk but together explain a significant proportion of genetic BC predisposition. For Hispanic women, the genetic contribution of SNPs to BC risk is not well understood. In these studies, we aim to develop and validate a polygenic score to improve risk assessment for Hispanic women who test negative for mutations in known BC susceptibility genes. Methods: Genotypes and clinical histories were collected from consecutive development and validation cohorts of patients referred for hereditary cancer testing. Study subjects include women who report strictly Hispanic or Latin American ancestry, and who test negative for mutations in 11 genes associated with breast cancer (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Based on a development cohort ascertained through June 2017, we evaluated an 86-SNP Residual Risk Score (RRS) that was previously developed and validated for women of European ancestry. In the same cohort we are developing a Hispanic Residual Risk Score (HRRS) optimized for women of Hispanic ancestry. BC associations of individual SNPs are being established through meta-analysis of the development cohort and published Hispanic studies. Multivariate logistic regression models were used to evaluate the 86-SNP RRS, and were the primary statistical tool for evaluation of individual SNPs and candidate polygenic scores. All models included personal/family cancer history and age as independent variables. P-values are based on likelihood ratio test statistics, and reported as two-sided. The development and validation studies are being conducted according to a protocol approved by the Quorum Institutional Review Board. Results: The development cohort included 5,454 Hispanic women, 24% of whom reported a personal history of BC. The 86-SNP RRS was significantly associated with a personal history of BC after accounting for personal and family cancer history (p&amp;lt;10-19) with odds ratio per unit standard deviation 1.39 (95% CI = 1.30-1.50). To date, more than 5,000 Hispanic women have been ascertained for inclusion in the validation cohort. Results comparing discriminatory accuracy of the RRS and the HRRS will be presented. Conclusions: The implementation of a clinically validated polygenic score may improve risk assessment and medical management of Hispanic women who test negative for monogenic BC mutations. The HRRS will be validated in an independent study population according to a pre-specified statistical analysis plan. Citation Format: Hughes ER, Wagner S, Pruss D, Gallagher SK, Swedlund B, Bulka K, Hoff R, Jammulapati S, Morris B, Perry T, Lanchbury JS, Gutin A. Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-02.

Abstract P5-09-08: Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients

Abstract Background: PARP inhibitors (PARPi) are FDA approved for a subset of metastatic human epidermal growth factor receptor 2-negative (H2N) breast cancer patients who harbor a germline pathogenic or likely pathogenic variant (PV) in BRCA1/2, two of the most well-described breast cancer susceptibility genes in the homologous recombination (HR) pathway. While the NCCN guidelines recommend consideration of BRCA1/2 testing for patients with H2N disease that are eligible for single-agent therapy, there are currently clinical trials available for women with advanced H2N breast cancer who have PVs in HR genes beyond BRCA1/2 to investigate outcomes of receiving PARPi. The yield of germline PVs in other HR genes in the H2N population is not well-described. Methods: Clinical histories and test results were reviewed for women with a diagnosis of H2N breast cancer who underwent multi-gene hereditary cancer panel testing that included a minimum of 10 homologous recombination (HR) genes in addition to BRCA1/2 (ATM, BARD1, BRIP1, CHEK2, FANCC, NBN, PALB2, PTEN, RAD51C, RAD51D). Those with prior BRCA1/2 testing were excluded. We assessed the yield of PVs in non-BRCA1/2 HR genes in the H2N breast cancer population. In addition, we compared the yield of PVs in non-BRCA1/2 HR genes in a “low risk” population (probands with H2N breast cancer with no reported personal history of ovarian or pancreatic cancer and no reported family history of breast, ovarian, pancreatic, or prostate cancer) to a “high risk” population (probands with H2N breast cancer who also have a personal history of ovarian or pancreatic cancer and/or a reported family history of breast, ovarian, pancreatic, or prostate cancer) via a two-tailed Fisher's exact test. Results: A total of 6179 women with H2N breast cancer were identified. Of these, BRCA1/2 PVs were identified in 4.8% (299/6179), while 5.7% (351/6179) carried PVs in HR genes other than BRCA1/2. These included CHEK2 (145), ATM (62), PALB2 (59), BRIP1 (26), FANCC (18), BARD1 (17), RAD51C (12), NBN (11), RAD51D (6), and PTEN (2). No statistically significant difference in the likelihood to harbor a PV in one of the 10 non-BRCA1/2 HR genes was observed between those with a “low risk” presentation (4.8% (53/1096) as compared to those with a “high risk” presentation (5.9% (298/5083)) (p=0.1956). Conclusions: Our findings show that the yield of PVs in HR genes other than BRCA1/2 is appreciable in the H2N breast cancer population. As such, it may be beneficial to include all HR genes when testing H2N breast cancer patients, regardless of other personal or family history, if and/or when a patient develops metastatic disease. Citation Format: Vogel Postula KJ, McGill AK, Sutcliffe E, Murphy PD, Klein RT, Hruska KS. Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-08.

Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing

ObjectiveWe explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory. MethodsThe combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression. ResultsFourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes. ConclusionsWomen with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.