Moderate Penetrance Genes Research Articles

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers.

High‐throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1530 patients with suspicion of hereditary predisposition to cancer, for which two types of analyses were performed: a) oriented according to the clinical presentation (n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer (n = 1113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer (P < .001) and in digestive cancers (P < .094) (respectively 15% vs 5% and 19.3%, vs 12.5%). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer.

Morphologic and molecular analysis of early-onset gastric cancer.

Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

ASO Author Reflections: Clinical Correlates of Moderate-Penetrance Genes in Breast Cancer.

ASO Author Reflections: Clinical Correlates of Moderate-Penetrance Genes in Breast Cancer.

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.

&lt;p&gt;Comparison of Patient Susceptibility Genes Across Breast Cancer: Implications for Prognosis and Therapeutic Outcomes&lt;/p&gt;

Hereditary breast cancer syndromes affect a small (10–15% of cases) but significant group of patients. BRCA1 and BRCA2 are the most familiar and well-studied genes associated with inherited breast cancer. However, mutations in the high-penetrance genes, TP53, PTEN, CDH1, MSH1, MLH1, MSH6, PMS2, PALB2, and STK11, and in the moderate-penetrance genes, CHEK2, ATM, and BRIP1, also correlate with high lifetime risks of breast cancer and other malignancies as well. Advances in breast cancer genetics have led to an improved perception of diagnosis and screening strategies. The specific considerations and challenges involved in treating this unique population have become a fertile ground for research. Indeed, these genes and downstream molecular pathways have now become potential therapeutic targets in breast cancer patients, including those with BRCA1 or BRCA2 mutations. This review describes the variety of hereditary breast cancer genes, from their molecular origins to the prognosis and multidisciplinary clinical decision-making processes. Key publications and other reported recent clinical trials and guidelines are provided.

Current Insights: Evolving Principles and Controversies of Cancer Risk Assessment and Management of Hereditary Cancers

With the introduction of panel and direct-to-consumer testing, genetic testing has become commonplace in recent years, paving the way for both increased awareness around prevalent genetic cancer risks, and also an onslaught of misinformation. At the NCCN 2020 Virtual Annual Conference, Dr. Tuya Pal led a panel of experts in discussing the utility and difficulties associated with multigene testing, the emerging role of moderate-penetrance genes in defining risks for hereditary cancer, and the controversies associated with direct-to-consumer genetic testing services.

Gene Mutations in Hereditary Breast Cancer- A Review

The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

ASTRO Radiation Therapy Summary of the ASCO-ASTRO-SSO Guideline on Management of Hereditary Breast Cancer

PurposeTo develop a summary of recommendations regarding locoregional management of patients with breast cancer and germline mutations in breast cancer susceptibility genes based on the American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology Guideline on Management of Hereditary Breast Cancer. MethodsThe American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an expert panel to develop recommendations based on a systematic review of the literature and a formal consensus process. A total of 58 articles met the eligibility criteria and formed the evidentiary basis for the locoregional therapy recommendations. Additionally, 6 randomized controlled trials of systemic therapy also met eligibility criteria. ResultsA joint evidence-based guideline was developed by a multidisciplinary panel, which has been separately published. From this guideline, the radiation-oncologist authors of the panel extracted pertinent surgical and radiation-specific recommendations of findings that are hereby presented. ConclusionsPatients with newly diagnosed breast cancer and BRCA1/2 mutations may be considered for breast conserving therapy (BCT), expecting similar rates of local control of the index cancer as noncarriers. The significant risk of contralateral breast cancer in these women (especially younger women), coupled with the higher risk of new cancers in the ipsilateral breast, warrant discussion of bilateral mastectomy. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or contralateral breast cancer events from radiation exposure in BRCA1/2 carriers. Patients with mutations in moderate-risk genes should be offered BCT as one choice after appropriate counseling. Radiation therapy should not be withheld in ATM carriers if BCT is planned. For patients with germline TP53 mutations, mastectomy is advised and radiation therapy is contraindicated except for those with a significant risk of locoregional recurrence.

Analysis of germline mutations in Chinese colorectal cancer patients with next-generation sequencing.

e13651 Background: Colorectal cancer (CRC) remains one of the leading causes of morbidity and mortality around the world. Familial cancer syndromes are common in CRC, inherited syndromes including Lynch syndrome (LS), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP) were well defined. But still, there are not well-established evidence between other several genes and CRC risk. Expanded multi-gene testing may be an alternative to find out the underlying mechanism for genetic susceptibility. Our study aims to assess the germline alternation landscape of Chinese CRC patients. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 381 genes on tissues from patients with CRC between January 01, 2017 and December 02, 2019 in 3D Medicines database. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: 1360 CRC patients were included for analysis, in which 95 (7.0%) patients harbored pathogenic (80/95) and likely pathogenic (15/95) germline mutations in 28 cancer predisposition genes. 33 subjects had pathogenic variants associated with Lynch syndrome (15 mutations in MLH1, 9 mutations in MSH2, 6 mutations in MSH6, 3 mutations in PMS2, respectively). 8 subjects had pathogenic variants associated with FAP (3 APC), MAP (3 MUTYH) and Li-Fraumeni syndrome (2 TP53). In addition, 14 pathogenic mutations in moderate penetrance genes (5 ATM, 3 BLM and 6 CHEK2) were found. The frequency of pathogenic BRCA mutations were 1 alternation in BRCA1 and 3 alternations in BRCA2. Conclusions: 7.0 % of patients with Chinese CRC carried germline cancer susceptibility gene mutations. Multi-gene testing would provide references for assessing genetic susceptibility and managing increased surveillance.

Development and validation of the PREMMplus clinical prediction model for multigene hereditary cancer risk assessment.

1579 Background: Current clinical prediction models provide syndrome-specific numeric estimates of an individual's likelihood of having a specific hereditary cancer syndrome (e.g., PREMM5 for Lynch syndrome; BRCAPRO for BRCA1/2). With the emergence of multigene panel testing (MGPT), there is a need to evaluate individuals' risk of carrying a pathogenic variant in a diverse array of cancer susceptibility genes in parallel. This study’s aim was to develop and validate the PREMMplus clinical prediction model for multigene cancer risk assessment. Methods: PREMMplus was developed in a cohort of 7296 individuals who had undergone germline MGPT at a single center. Logistic regression models were used to examine candidate predictive variables – including age, sex, ethnicity, and personal/family history of cancer – to provide a numeric estimate of an individual’s likelihood of carrying a pathogenic/likely pathogenic germline variant in one of 18 cancer susceptibility genes (11 high- [ APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and 7 moderate-penetrance [ ATM, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in an independent dataset of 14845 individuals who had undergone MGPT at a commercial laboratory. Results: Using clinical characteristics, including personal/family history of 18 cancers plus colorectal adenoma burden, PREMMplus demonstrated an excellent ability to predict pathogenic variants in high penetrance genes at 90% sensitivity. PREMMplus had acceptable performance with the addition of 7 moderate penetrance genes. PREMMplus was well-calibrated and demonstrated comparable performance in the external validation dataset. Conclusions: PREMMplus is the first validated risk assessment model to quantify an individual’s likelihood of carrying pathogenic variants in a wide diversity of cancer risk genes, and can be used to select individuals who should undergo MGPT. As expected, PREMMplus’s discriminatory capacity was reduced with the inclusion of moderate penetrance cancer risk genes. [Table: see text]

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Abstract P2-09-01: Clinicopathological features and surgical management trends in individuals with breast cancer and deleterious mutations in moderate penetrance genes

Abstract Background: Moderate penetrance genes - ATM, CHEK2, and PALB2 - are often included in hereditary cancer panel testing as mutations have been linked to familial breast cancer. Limited data exists on breast cancer presentation and surgical management. We aimed to review clinicopathological features of breast cancers in patients affected by these mutations and trends in surgical management compared to unaffected cancer patients. Methods: We conducted a retrospective review of breast cancer patients, stage 0 to III, with deleterious mutations in ATM, CHEK2, and PALB2 between 2007 and 2017 at a tertiary institution. Data collected included demographics, clinicopathological tumor features, and type of treatment. These patients were compared to a control group of sporadic breast cancer patients referred for genetic counseling who tested negative for deleterious mutations via panel testing. Chi-square test, t-test, and stepwise logistic regression were used for statistical analysis. Results: A total of 145 patients had breast cancer (144 women and 1 male). There were 74 mutation-positive patients (24 ATM, 26 CHEK2, 24 PALB2) and 71 mutation-negative patients (Table 1). No differences were found in age or ethnicity among both groups. Mutation-positive patients had a higher rate of family members affected by breast cancer (79.7% vs. 52.9% in mutation-negative, p=0.0006), and tumors greater than 2 cm (63.1% vs. 42.3% in mutation-negative, p=0.0152). No differences were found on tumor histopathology, use of radiotherapy, and use of chemotherapy/endocrine therapy between the two groups. Of the patients harboring mutations, 55 patients received surgical treatment for their breast cancer after discovery of their mutation status, while the rest had surgery performed prior to genetic testing. All controls received surgery as part of treatment. Significant differences were seen in type of surgery chosen in each group. There was a lower rate of breast-conserving surgery in the mutation-positive group (25.5% vs. 46.5% in mutation-negative, p=0.0155). Additionally, 65.5% of mutation-positive patients underwent contralateral prophylactic mastectomy (CPM) compared to 33.3% in mutation-negative patients (p=0.0004). There was no association between age or ethnicity and choice of CPM. Conclusions: Mutation-positive patients are more likely to have positive family histories and larger tumors at diagnosis. They also have a higher rate of mastectomy and double the rate of CPM compared to those unaffected by mutations in moderate penetrance genes. These patients opt for more radical surgical treatment despite lack of clear guidelines for this approach. Further studies are needed to better advise physicians and patients regarding treatment decisions when encountering these mutations. Table 1. Patient, tumor, and treatment characteristicsMutationaNo mutationN=74N=71P-valueAge at diagnosis, mean (SD)48.43 (10.47)50.82 (9.84)0.1601no. (%)no. (%)EthnicityWhite49 (66.2)45 (63.4)0.8839Hispanic15 (20.3)13 (18.3)Black8 (10.8)11 (15.5)Asian2 (2.7)2 (2.8)Family history of breast cancerbYes50 (79.7)37 (52.9)0.0006No15 (20.3)33 (47.1)Stagec0 and I23 (33.8)35 (49.3)0.0644II and III45 (66.2)36 (50.7)Tumor sizec (cm)≤ 224 (36.9)41 (57.7)0.0152&amp;gt; 241 (63.1)30 (42.3)Lymph nodecPositive24 (36.4)26 (36.6)0.9752Negative42 (63.6)45 (63.4)Nuclear gradeI9 (15.8)14 (20.0)0.8284II23 (40.4)27 (38.6)III25 (43.9)29 (41.4)Estrogen receptorPositive56 (84.8)53 (74.6)0.1390Negative10 (15.2)18 (25.4)HER2/Neu receptorPositive17 (26.2)14 (19.7)0.3715Negative48 (73.8)57 (80.3)HistologyDuctal69 (93.2)63 (88.7)0.3419Lobular5 (6.8)8 (11.3)KI-67 proliferation index≤ 2017 (34.0)22 (36.7)0.7710&amp;gt; 2033 (66.0)38 (63.3)Use of chemotherapyYes47 (67.1)45 (63.4)0.6390No23 (32.9)26 (36.6)Adjuvant radiotherapyYes42 (59.2)40 (56.3)0.7340No29 (40.8)31 (43.7)Adjuvant endocrine therapyYes45 (65.2)53 (74.6)0.2235No24 (34.8)18 (25.4)Type of surgeryBCSd14 (25.5)33 (46.5)0.0155TMd41 (74.5)38 (53.5)Contralateral prophylactic mastectomy (CPM)CPM36 (65.5)23 (33.3)0.0004No CPM19 (34.5)46 (66.7)(a). ATM, CHEK2, PALB2, (b) First and second-degree relatives, (c) Tumor size, lymph node status, and stage assessed clinically, (d) Abbreviations: BCS = breast-conserving surgery, TM = total mastectomy Citation Format: Colton Pence, Jordan Berg, Natalia Partain, Navid Sadeghi, Caitlin Mauer, Sara Pirzadeh-Miller, Ang Gao, Hsiao Li, Nisha Unni, Samira Syed. Clinicopathological features and surgical management trends in individuals with breast cancer and deleterious mutations in moderate penetrance genes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-01.

Abstract PD3-02: Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study

Abstract Background: Pathogenic variants detected in multi-gene cancer predisposition panels are increasingly used to counsel women regarding their risk for breast cancer. However, the clinical implications of moderate penetrance genes (e.g. CHEK2, ATM) remain unclear. Breast MRI is indicated for women with a lifetime risk of breast cancer of &amp;gt;20%, and polygenic risk scores (PRS) based on common variants discovered in recent genome-wide association studies (GWAS) may identify women with pathogenic variants in CHEK2 and ATM who are above or below this level of risk. PRS may also stratify carriers with substantially elevated lifetime risks of breast cancer. Previous work found that PRS modified breast cancer risk in carriers of pathogenic variant in BRCA1 or BRCA2, but the joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no published study evaluating the effect of PRS among women with pathogenic variants in genes other than BRCA1/2 and CHEK2. Here, we evaluated the joint effects of PRS and pathogenic variants in ten established breast cancer predisposition genes in a population-based case-control sample. Method: We analyzed 43,144 non-Hispanic European-ancestry individuals (20,988 controls and 22,120 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using a dual bar-coded QIAseq panel of breast cancer predisposition genes. Variant calling was conducted with Haplotype Caller and Vardict. The PRS was calculated based on 106 common variants using effect estimates from the largest published breast cancer GWAS. Genetic status was evaluated for 10 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NF1, PALB2 and TP53. Lasso Penalized regression was performed to assess the combined effect on overall breast cancer of pathogenic variants and common variants (including main and interaction effects between age, family history, carrier status and PRS). The fraction of women at &amp;gt;2-fold increased risk (which is associated with approximately 20% lifetime risk of breast cancer) was calculated for pathogenic variant carriers and non-carriers of different family history and age groups (&amp;lt;40, 40-50, 50-60, 60-70, &amp;gt;70yrs old). Results: Among non-carriers, one standard deviation change in the PRS was associated with a 1.63x change in odds of breast cancer. The best-fitting risk model did not include any PRS-by-carrier interaction terms, implying the relative risk gradient associated with PRS among women with pathogenic variants is similar to that among non-carriers. For carriers of pathogenic variants in moderate penetrance genes with no family history of breast cancer, the PRS can identify 60.6% of ATM pathogenic variant carriers and 30% of CHEK2 pathogenic variant carriers that have less than 2-fold risk of breast cancer; when carriers have a family history of breast cancer, the PRS can identify 30% of ATM pathogenic variant carriers and 11.8% of CHEK2 pathogenic variant carriers with less than 2-fold risk of breast cancer. Conclusion: In our large, population-based case-control study, the effect of the PRS among pathogenic variant carriers was not significantly different than among non-carriers. However, the PRS may be particularly important for estimating breast cancer risk among carriers of pathogenic variants in moderate penetrance genes such as CHEK2 and ATM, enabling a more precise approach for MRI screening strategy and breast cancer risk management. Citation Format: Chi Gao, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jie Na, Nicholas J. Boddicker, Raed Samara, Paul Auer, Leslie Bernstein, Mia Gaudet, Amy Trentham-Dietz, Song Yao, Christopher Haiman, Janet E. Olson, Susan Neuhausen, Jeffrey N. Weitzel, David E. Goldgar, Susan Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft, on behalf of the CARRIERS consortium. Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-02.

Abstract P6-08-07: Polygenic breast cancer risk modification in carriers of high and intermediate risk gene mutations

Abstract Background: The incorporation of polygenic scores into breast cancer risk assessment models has led to improved risk management for women of European ancestry. However, few studies have examined the extent to which polygenic scores modify risk for carriers of breast cancer susceptibility gene mutations. Current literature suggests that a 77-SNP polygenic score developed from large, mainly non-carrier general population studies can stratify breast cancer risk for carriers of the CHEK2 founder mutation 1100delC with the same effect size observed for non-carriers. Consequently, several groups have modified risk estimates for carriers of other pathogenic variants by applying published effect estimates from non-carriers. In a recent study, a similar 88-SNP polygenic score showed reduced effectiveness in BRCA1 and BRCA2 carriers compared to non-carriers. This highlights the need for more information on polygenic score performance among women who carry pathogenic variants in ATM or PALB2, or in CHEK2 other than the 1100delC founder mutation. We previously described an 86-SNP polygenic residual risk score (RRS) that characterizes genetic risk which is not due to high- or moderate-penetrance breast cancer gene mutations. Here, we present pre-specified independent validation of the RRS for BRCA1, BRCA2, CHEK2, ATM and PALB2 carriers.Methods: This IRB-approved study included 152,172 women of European ancestry who were tested clinically for hereditary cancer risk with a multi-gene panel. The RRS was evaluated separately for carriers of BRCA1 (N=2,249), BRCA2 (N=2,638), CHEK2 (N=2,564), ATM (N=1,445) and PALB2 (N=906), and for mutation-free women (N=141,160). Clinical information was obtained from test requisition forms. Multivariable logistic regression was used to examine the association of RRS with invasive breast cancer after accounting for age and family cancer history. Effect sizes, expressed as standardized odds ratios (ORs) with 95% confidence intervals (CIs), were assessed for carriers of each gene and for non-carriers. Results: RRS was strongly associated with breast cancer risk in each of the BRCA1, BRCA2, CHEK2, ATM and PALB2 carrier populations (p&amp;lt;10−4). Risk modification in CHEK2 carriers (OR 1.49; CI 1.36-1.64) was consistent with that observed in non-carriers (OR 1.47; CI 1.45-1.49). CHEK2 carriers in the highest RRS quintile had approximately 1.7-fold higher risk than the middle quintile (OR 1.67; CI 1.26 - 2.20), and the lowest quintile had risk lowered by factor of 0.59 (OR 0.59; CI 0.44 - 0.80). We observed reduced modification similar to existing literature for carriers of BRCA1 (OR 1.20; CI 1.10-1.32) and BRCA2 (OR 1.23; CI 1.12-1.34). Odds ratios for ATM (1.37; CI 1.21-1.55) and PALB2 (1.34; CI 1.16-1.55) had wide confidence intervals that overlapped those for the other carrier populations. Discussion: The RRS significantly modifies risk for carriers of BRCA1, BRCA2, CHEK2, ATM and PALB2 mutations albeit with apparently different effect sizes. These results indicate that risk estimates employing polygenic scores may need to be derived separately for each gene. Given the modest effect on BRCA1 and BRCA2 risk and the substantial risks conferred by these genes even with lower RRS, the clinical implications of polygenic modification in this setting are yet to be determined. In CHEK2 carriers, we observed strong polygenic modification similar to that achieved for non-carriers. For ATM and PALB2, larger studies are needed to refine polygenic effect size estimates. Comprehensive risk assessment combining RRS with family cancer history and other risk factors has potential to refine risk estimates and facilitate decision-making for women with mutations in moderate penetrance genes. Citation Format: Shannon Gallagher, Elisha Hughes, Susanne Wagner, Placede Tshiaba, Eric Rosenthal, Benjamin B. Roa, Allison Kurian, Susan Domchek, Judy Garber, Johnathan M. Lancaster, Jeffrey Weitzel, Alexander Gutin, Jerry S. Lanchbury, Mark Robson. Polygenic breast cancer risk modification in carriers of high and intermediate risk gene mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-07.

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

Factors that impact risk management decisions among women with pathogenic variants in moderate penetrance genes associated with hereditary breast cancer.

There is limited information known about how women with pathogenic variants (PV) in moderate penetrance genes make decisions to manage their increased risk of breast cancer. This study analyzed factors that may impact decision-making surrounding management for increased breast cancer risk. Women with a PV in a moderate penetrance gene associated with increased risk for breast cancer were identified from an institutional database. Semi-structured, qualitative interviews were conducted to analyze decision-making factors. Themes were developed using deductive codes based on previous literature and inductive codes based on interviewee responses. The 16 participants (mean age=55.9years) included 12 women with a breast cancer diagnosis. Six women (37.5%) chose bilateral mastectomy (BM), and 10 women (62.5%) chose surveillance as management. Of the 12 women with a personal history of breast cancer, four chose to have BM (33.3%). Two women without a personal history of breast cancer chose to have BM (50.0%). Transcriptions revealed seven comprehensive themes, as well as themes unique to affected and unaffected women (Cohen's kappa=0.80). Physician opinion was the only factor present in all interviews reported to influence risk management decision-making. Several themes were consistent with prior BRCA1/BRCA2 research (family history, risk perception, sibling influence, and physician opinions). Autonomy and insurance/finances were also important factors to participants. There were certain differences in decision-making factors between affected and unaffected women, such as partner influence. Results indicate an opportunity for providers to engage their patients in a decision-making process.

Referencing BRCA in hereditary cancer risk discussions: In search of an anchor in a sea of uncertainty.

As panel testing and exome sequencing are increasingly incorporated into clinical care, clinicians must grapple with how to communicate the risks and treatment decisions surrounding breast cancer genes beyond BRCA1 and BRCA2. In this paper, we examine clinicians' practice of employing BRCA1 and BRCA2 to help contextualize less certain genetic information regarding cancer risk and the possible implications of this practice for patients within the context of an exome sequencing study, NCGENES. We audio-recorded return of results appointments for 14 women who participated in NCGENES, previously had breast cancer, and were suspected of having a hereditary cancer predisposition. These patients were also interviewed four weeks later regarding their understanding of their results. We found that BRCA1 and BRCA2 were held as the gold standard, where clinicians compared what is known about BRCA to the limited understanding of other breast cancer-related genes. BRCA1 and BRCA2 were used as anchors to shape patients' understandings of genetic knowledge, risk, and management, illustrating how the information clinicians provide to patients may work as an external anchor. Yet, presenting BRCA1 and BRCA2 as a means of scientific reassurance can run the risk of patients conflating knowledge about certainty of risk with degree of risk after receiving a result for a moderate penetrance gene. This can be further complicated by misperceptions of the precision of cancer predictability attributed to these or other described 'cancer genes' in public media.

Breast cancer screening implications of risk modeling among female relatives of ATM and CHEK2 carriers.

With the increasing use of multigene panel tests, pathogenic and likely pathogenic (P/LP) variants are identified more frequently in the moderate-penetrance breast cancer genes ATM and CHEK2. Lifetime breast cancer risk among women with P/LP variants in these genes generally exceeds 20%, meeting the threshold at which high-risk breast cancer screening through breast magnetic resonance imaging (MRI) is recommended. Among a registry-based sample of 56 ATM and 69 CHEK2 carriers, the authors sought to determine the percentage of relatives in whom a P/LP variant would impact breast cancer surveillance. Lifetime breast cancer risks for unaffected, female first-degree and second-degree relatives were estimated using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Among first-degree relatives of ATM and CHEK2 carriers, only 22.6% and 14.9%, respectively, were found to have lifetime breast cancer risks of ≥20% based on family cancer history alone; however, when including the proband's P/LP variant in the model, these percentages increased significantly to 56.6% and 55.3%, respectively (P<.0001 and P<.0001, respectively). Similar increases in lifetime breast cancer risks were found among second-degree relatives. The results of the current study suggest that the majority of female first-degree and second-degree relatives of ATM and CHEK2 carriers do not qualify for breast MRI based on family cancer history alone. Therefore, testing for these genes, as well as awareness of positive moderate-penetrance breast cancer gene results in the family, may impact MRI eligibility. These findings highlight the potential usefulness of and need for breast cancer risk models that incorporate moderate-penetrance gene positivity to inform screening recommendations among at-risk family members.

Increased Risk of Acute Myelogenous Leukemia After Early Onset but Not Late-Onset Colorectal Cancer.

Early onset colorectal cancer in persons younger than 50 years is increasingly common. Clinical and molecular characterizations reveal a distinctive disease. Thirty percent of patients have mutations of hereditary cancer syndromes, especially Lynch syndrome. A recent analysis, testing germline DNA for mutations in 25 cancer susceptibility genes, showed that some patients younger than 50 years had mutations of high-penetrance colorectal cancer genes such as APC (adenopolyposis coli). Others had mutations in high-penetrance or moderate-penetrance genes not traditionally associated with colorectal cancer, such as ATM (ataxia telangiectasia mutated), whereas still others had low penetrance colorectal cancer genes. In the current study, we examined the incidence of second cancers following early onset (age less than 50 y) colorectal cancer. The initial study population was assembled using records from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER*Stat MP-SIR (multiple primary-standardized incidence ratio) tool was used to calculate SIRs and excess risk for second primary malignancies. The SIR is expressed as the ratio of observed-to-expected (O/E) cases. We used The Cancer Genome Atlas (TCGA) and AACR Project Genie for genetic analysis. The data were accessed with the online Xena Browser and cBioportal. Acute myelogenous leukemia (AML) O/E ratios were significantly >1 in patients aged less than 50 years, at 12 to 59 months after colorectal cancer. In patients aged 50 years and older, O/E ratios were equal to 1 or quite close at 12 to 59 months after colorectal cancer. Alterations in 3 AML genes, CEBPA-AS1, MLLT1, and MLLT6, affected the prognosis of colorectal cancer patients less than 50 years but not older than 50 years. One AML gene, FLT3, had the highest copy number alteration frequency of any gene in 1438 colorectal patients 18 to 48 years of age. Genetic alterations of FLT3/TP53 were mutually exclusive. Genetic alterations of FLT3/JAK2 and JAK2/CTNNB1 were co-occurrent. These observations suggest that early onset colorectal cancer and AML may be related diseases.