Moderate Penetrance Genes Research Articles

Racial and Ethnic Differences in BRCA1/2 and Multigene Panel Testing Among Young Breast Cancer Patients

Genetic testing for hereditary breast and ovarian cancer (HBOC) is recommended for breast cancer patients diagnosed at age ≤ 50 years. Our objective was to examine racial/ethnic differences in genetic testing frequency and results among diverse breast cancer patients. A retrospective cohort study among women diagnosed with breast cancer at age ≤ 50 years from January 2007 to December 2017 at Columbia University in New York, NY. Among 1503 diverse young breast cancer patients, nearly half (46.2%) completed HBOC genetic testing. Genetic testing completion was associated with younger age, family history of breast cancer, and earlier stage, but not race/ethnicity or health insurance status. Blacks had the highest frequency of pathogenic/likely pathogenic (P/LP) variants (18.6%), and Hispanics and Asians had the most variants of uncertain significance (VUS), 19.0% and 21.9%, respectively. The percentage of women undergoing genetic testing increased over time from 15.3% in 2007 to a peak of 72.8% in 2015. Over the same time period, there was a significant increase in P/LP and VUS results. Due to uncertainty about the clinical implications of P/LP variants in moderate penetrance genes and VUSs, our findings underscore the need for targeted genetic counseling education, particularly among young minority breast cancer patients.

Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.

Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.

Multigene Cancer Panels: Implications for Pre- and Post-test Genetic Counseling

The availability of multigene cancer panel testing (MCPT) has revolutionized the care of individuals and families at risk for hereditary cancer. This review discusses fundamental components of genetic counseling, test selection, result interpretation, and follow-up related to MCPT. Routine use of MCPT increases the diagnostic yield for major hereditary cancers such as breast, ovarian, and colon, with the identification of pathogenic variants in high- and moderate-penetrance genes. In addition, the larger the panel, the more likely one or more variants of uncertain significance will be identified. Furthermore, although index cases who test negative after multigene panel testing may derive some reassurance about hereditary risk, assessment and management based on personal and family history are the keys. Given the complexity of MCPT, pre- and post-test genetic counseling approaches have been adapted to optimize the delivery of information and support to patients and their families.

424P - Cancer worry, genetic knowledge, and attitudes towards NGS multigene panel testing among Korean breast cancer patients

BackgroundRecent advances in next generation sequencing technology helped us to test multiple germline genetic mutations simultaneously. However, because of the low frequency of pathogenic/ likely pathogenic variants beyond BRCA1/2, modest risk of cancer in the carriers of moderate penetrance genes, and lack of proper preventive strategies for the carriers, clinical application of NGS multiple panel tests still has limitations. MethodsIn this study, we provided sequential genetic testing and counselling programs for BRCA1/2 mutation tests and multigene panels beyond BRCA, and investigated cancer worry, genetic knowledge, and attitude towards gene panels among the patients. ResultsAs of 28 February 2019, we prospectively enrolled 149 Korean BRCA1/2 mutation-negative female breast cancer patients with high risk for hereditary breast cancer. Median age of the patients was 42.9 (range, 21.9∼74.5) years. Among the patients, we identified 15 cases with pathogenic/ likely pathogenic variants. After genetic counselling about multigene panel, patients showed slightly decreased concern about the possibility of cancer in the future (average score of pre-, 4.32±0.808 to post-, 4.07±1.017; P = 0.003) and lower influence on mood (average score of pre-, 3.31±0.669 to post-, 3.19±0.684; P = 0.005). However, there were no changes in the average score of genetic knowledge (pre-, 0.68±0.212 to post-, 0.69±0.214; P = 0.465), and the impact of cancer worries on daily activities (pre-, 3.06±0.810 to post-, 2.97±0.699; P = 0.074). In the survey on multigene panel, 143 (96.0%) patients reported that genetic testing and counseling about multigene panel were very much (55.0%) or much (40.9%) helpful for the patients and family. 63 (42.3%) patients wanted concurrent application of BRCA1/2 mutation testing and multigene testing beyond BRCA, and 71 (47.7%) patients wanted sequential application of the tests. ConclusionsMultigene panel testing and genetic counselling may help to decrease cancer worry about the possibility of cancer in the future in BRCA1/2 mutation-negative patients with high risk for hereditary breast cancer. We need to find the appropriate sequence and methods for NGS multigene panel testing and counselling programs. Legal entity responsible for the studyThe authors. FundingNational Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT)(NRF-2018R1C1B6009449). DisclosureAll authors have declared no conflicts of interest.

Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact.

Nowadays CHK2 mutation is studied frequently in hereditary breast and ovarian cancer patients in addition to BRCA1/BRCA2. CHK2 is a tumor suppressor gene that encodes a serine/threonine kinase, also involved in pathways such as DNA repair, cell cycle regulation and apoptosis in response to DNA damage. CHK2 is a well-studied moderate penetrance gene that correlates with third high risk susceptibility gene with an increased risk for breast cancer. Hence before planning large population study, it is better to scrutinize putative functional SNPs of CHK2 using different computational tools. In this study, we have used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of CHK2 protein that might be causing this disease. Computational analysis was performed by different in silico tools including SIFT, Align GVGD, SNAP-2, PROVEAN, Poly-Phen-2, PANTHER, PhD-SNP, MUpro, iPTREE-STAB, Consurf, InterPro, NCBI Conserved Domain Search tool, ModPred, SPARKS-X, RAMPAGE, Verify-3D, FT Site, COACH and PyMol. Out of 78 nsSNP of human CHK2 gene, seven nsSNPs were predicted functionally most significant SNPs. Among these seven nsSNP, p.Arg160Gly, p.Gly210Arg and p.Ser415Phe are highly conserved residues with conservation score of 9 and three nsSNP were predicted to be involved in post translational modification. The p.Arg160Gly and p.Gly210Arg may interfere in phosphopeptide binding site on FHA conserved domain. The p.Ser415Phe may interfere in formation of activation loop of protein-kinase domain and might interfere in interactions of CHK2 with ligand. The study concludes that mutation of serine to phenylalanine at position 415 is a major mutation in native CHK2 protein which might contribute to its malfunction, ultimately causing disease. This is the first comprehensive study, where CHK2 gene variants are analyzed using in silico tools hence it will be of great help while considering large scale studies and also in developing precision medicines related to these polymorphisms in the era of personalized medicine.

Clinical Management of Patients at Risk for Hereditary Breast Cancer with Variants of Uncertain Significance in the Era of Multigene Panel Testing

Rising use of multigene panel testing has led to increased identification of variants of uncertain significance (VUS). Consensus guidelines state that clinicians should not make medical management decisions based on VUS findings. We sought to analyze how VUS affect management of patients at risk for hereditary breast cancer. All genetic testing reports for indications of hereditary breast cancer risk from a single tertiary-care institution from 2015 to 2018 were reviewed. Variants were grouped by pathogenicity (benign/likely benign, VUS, or pathogenic/likely pathogenic [P/LP]) and by breast cancer susceptibility (high, moderate, or none). Patient and management characteristics were compared by variant pathogenicity and breast cancer risk. Overall, 563 patients underwent genetic testing for breast cancer risk; 336 VUS were identified in 228 (40.5%) of patients of which 26.4% were in high or moderate penetrance genes. P/LP results were found in 61 (10.8%) patients, of which 61.2% were identified in breast-specific moderate and high penetrance genes, and 38.7% were found in non-breast specific genes. Of variants found in high-risk genes, 54.5% were P/LP and 45.5% were VUS. On multivariable analysis, prophylactic mastectomy was associated with younger age and personal history of cancer, but not variant pathogenicity or penetrance. There were no differences in the use of post-test imaging, oophorectomy, or colonoscopy based on variant findings or age. In this era of multigene panel testing, genetic factors help to inform, but not dictate, complex decision-making in surveillance and management of patients at risk for hereditary breast cancer.

Abstract 729: Zygosity, lineage, and penetrance dictate the role of germline pathogenicity in tumorigenesis

Abstract Human cancers arise from environmental, heritable, and somatic factors. While each has been studied extensively, how these factors interact to drive tumorigenesis and disease phenotypes is poorly understood. Here, we integrated germline pathogenicity with somatic alterations inferred from the prospective sequencing of 17,152 advanced cancer patients across 55 cancer types to explore their interplay in tumorigenesis. Leveraging expert curated germline variant calls from 5,358 patients, we developed a combined machine learning and risk stratification-based approach for pathogenicity assessment. Overall, 10.3% of patients harbored a pathogenic allele with penetrance levels ranging from high to low, and an additional 6.3% with a variant of uncertain penetrance. Integrating high-precision zygosity inference in the concomitant cancer diagnoses, we found that only carriers of high penetrance germline pathogenic alleles that are biallelically inactivated in their tumors had an earlier age of onset (51y in carriers vs. 58y in germline WT, p-value=3.5e-12), and an elevated rate of multiple independent cancer diagnoses (23% in carriers vs 13% in germline WT, p-value=1.6e-7). Broadly, penetrance dictated somatic dependence, with only those higher penetrant germline pathogenic alleles associated with lineage-dependent selective pressure for somatic biallelic inactivation (p-value<2e-16). Tumor lineage dictated the substantial variability in the rate of tumor-specific biallelic inactivation of germline alleles, even among high penetrance genes. Among only high and moderate penetrance genes, high-risk cancers for which these alleles predispose and are therefore strongly associated by prevalence had the highest biallelic inactivation rates as compared to those for which no association exists (85 versus 30%, respectively; p-value<2e-16). Consequently, nearly 30% of all tumors diagnosed in carriers of high penetrance germline alleles are likely sporadic cancers whose tumorigenesis is unrelated to the germline dysfunction. Moreover, tumorigenesis in only those carriers of high penetrance germline alleles biallelically inactivated in their tumors required fewer somatic oncogenic driver mutations overall to confer a selective growth advantage, emphasizing their distinct role as a founding event in disease pathogenesis. Collectively, the role of germline pathogenicity in tumorigenesis is determined by penetrance and zygosity in a manner that is lineage-dependent, thereby facilitating the discovery of true germline drivers and multiple distinct routes to tumorigenesis in affected patients, with implications for disease pathogenesis, screening, and ultimately therapy. Citation Format: Chaitanya Bandlamudi, Preethi Srinivasan, Philip Jonsson, Yelena M. Kemel, Shweta S. Chavan, Allison L. Richards, Alex Penson, Craig M. Bielski, Chris Fong, Aijazuddin Syed, Gowtham Jayakumaran, Meera Prasad, Jason Hwee, Nikolaus Schultz, Semanti Mukherjee, Vijai Joseph, Diana Mandelkar, Ozge Birsoy, Liying Zhang, Jinru Shia, Ahmet Zehir, Marc Ladanyi, David M. Hyman, Kenneth Offit, Mark E. Robson, David B. Solit, Zsofia K. Stadler, Michael F. Berger, Barry S. Taylor. Zygosity, lineage, and penetrance dictate the role of germline pathogenicity in tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 729.

Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer.

PURPOSELittle is known about the genetic predisposition to breast and ovarian cancer among the Chilean population, in particular genetic predisposition beyond BRCA1 and BRCA2 mutations. In the current study, we aim to describe the germline variants detected in individuals who were referred to a hereditary cancer program in Santiago, Chile.METHODSData were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results.RESULTSThree hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non-BRCA1/2 genes.CONCLUSIONTesting for non-BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

Psychosocial Effects of Multigene Panel Testing in the Context of Cancer Genomics.

In recent years, with both the development of next-generation sequencing approaches and the Supreme Court decision invalidating gene patents, declining costs have contributed to the emergence of a new model of hereditary cancer genetic testing. Multigene panel testing (or multiplex testing) involves using next-generation sequencing technology to determine the sequence of multiple cancer-susceptibility genes. In addition to high-penetrance cancer-susceptibility genes, multigene panels frequently include genes that are less robustly associated with cancer predisposition. Scientific understanding about associations between many specific moderate-penetrance gene variants and cancer risks is incomplete. The emergence of multigene panel tests has created unique challenges that may have meaningful psychosocial implications. Contrasted with the serial testing process, wherein patients consider the personal and clinical implications of each evaluated gene, with multigene panel testing, patients provide broad consent to whichever genes are included in a particular panel and then, after the test, receive in-depth genetic counseling to clarify the distinct implications of their specific results. Consequently, patients undergoing multigene panel testing may have a less nuanced understanding of the test and its implications, and they may have fewer opportunities to self-select against the receipt of particular types of genetic-risk information. Evidence is conflicting regarding the emotional effects of this testing.

Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.

Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.

Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing

Since the discovery of BRCA1 and BRCA2, multiple high- and moderate-penetrance genes have been reported as risk factors for hereditary breast cancer, ovarian cancer, or both; however, it is unclear whether these findings represent the complete genetic landscape of these cancers. Systematic investigation of the genetic contributions to breast and ovarian cancers is needed to confirm these findings and explore potentially new associations. To confirm reported and identify additional predisposition genes for breast or ovarian cancer. In this sample of 11 416 patients with clinical features of breast cancer, ovarian cancer, or both who were referred for genetic testing from 1200 hospitals and clinics across the United States and of 3988 controls who were referred for genetic testing for noncancer conditions between 2014 and 2015, whole-exome sequencing was conducted and gene-phenotype associations were examined. Case-control analyses using the Genome Aggregation Database as a set of reference controls were also conducted. Breast cancer risk associated with pathogenic variants among 625 cancer predisposition genes; association of identified predisposition breast or ovarian cancer genes with the breast cancer subtypes invasive ductal, invasive lobular, hormone receptor-positive, hormone receptor-negative, and male, and with early-onset disease. Of 9639 patients with breast cancer, 3960 (41.1%) were early-onset cases (≤45 years at diagnosis) and 123 (1.3%) were male, with men having an older age at diagnosis than women (mean [SD] age, 61.8 [12.8] vs 48.6 [11.4] years). Of 2051 women with ovarian cancer, 445 (21.7%) received a diagnosis at 45 years or younger. Enrichment of pathogenic variants were identified in 4 non-BRCA genes associated with breast cancer risk: ATM (odds ratio [OR], 2.97; 95% CI, 1.67-5.68), CHEK2 (OR, 2.19; 95% CI, 1.40-3.56), PALB2 (OR, 5.53; 95% CI, 2.24-17.65), and MSH6 (OR, 2.59; 95% CI, 1.35-5.44). Increased risk for ovarian cancer was associated with 4 genes: MSH6 (OR, 4.16; 95% CI, 1.95-9.47), RAD51C (OR, not estimable; false-discovery rate-corrected P = .004), TP53 (OR, 18.50; 95% CI, 2.56-808.10), and ATM (OR, 2.85; 95% CI, 1.30-6.32). Neither the MRN complex genes nor CDKN2A was associated with increased breast or ovarian cancer risk. The findings also do not support previously reported breast cancer associations with the ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D, or mismatch repair genes MSH2 and PMS2. The results of this large-scale exome sequencing of patients and controls shed light on both well-established and controversial non-BRCA predisposition gene associations with breast or ovarian cancer reported to date and may implicate additional breast or ovarian cancer susceptibility gene candidates involved in DNA repair and genomic maintenance.

Moderate-Penetrance Predisposition to Breast Cancer

Research over the past 25 years has revealed much about the architecture of predisposition to breast and ovarian cancer. There is now a general understanding that there are three broad categories of germline variation that may increase risk. First, there are the “high-penetrance” genes associated with a relative risk for cancer of greater than 5 and demonstrating an autosomal dominant pattern of inheritance. At the other end of the spectrum are “low-penetrance” common variants. These variants are associated with minor increases in risk (commonly less than a relative risk of 1.5). The third group of genes are “moderate-penetrance” genes, with pathogenic variants seen rarely in the general population (commonly < 1%) and relative risks for cancer generally between 2 and 5. Moderate-penetrance genes are the focus of this review. With the advent of multigene panel testing based on next-generation (or massively parallel) sequencing, genetic risk assessment is identifying significant numbers of patients with pathogenic variants in moderate-penetrance genes such as CHEK2, ATM, PALB2, BRIB1, RAD51C, RAD51D, BARD1, and NBN. Risks associated with breast, ovarian, and other cancers are emerging. The strength of associations between many of these “moderate-penetrance” genes and cancer risk remains somewhat unclear. Risk is likely to be modulated by age, family history, and perhaps specific genotype, further complicating the clinical counseling scenario. There is a clear need for ongoing research in this area, an endeavor that is likely to take time and commitment given the relative rarity of these pathogenic variants.

Absence of the CHEK2 c.1100delC mutation in familial breast and ovarian cancer in Colombia: a case-control study

Background: BRCA1 and BRCA2 have been identified as high-penetrance breast cancer predisposition genes, but they only account for a small fraction of the inherited component of breast cancer. To explain the remaining cases, a polygenic model with a large number of low- to moderate-penetrance genes have been proposed; one of these, is the CHEK2 gene (Checkpoint Kinase 2). The objective of this study was to determine the role of the CHEK2 gene, specifically the c.1100delC mutation in familial breast cancer susceptibility in Colombian patients. Methods: We screened 131 high-risk breast and/or ovarian cancer patients (negative for mutations in BRCA1 and BRCA2) and 131 controls for the germline mutation CHEK2 c.1100delC by allele-specific PCR. Results: None of the cases or controls showed the CHEK2 c.1100delC mutation, neither as a homozygote nor as a heterozygote. Conclusions: Our results suggest that the CHEK2 c.1100delC mutation is not a risk factor for genetic susceptibility to familial breast or ovarian cancer in the Colombian population. The absence of the CHEK2 c.1100delC mutation in our population show the importance of considering ethnic background before offering a genetic test.

Abstract B77: Panel testing to evaluate genetic predisposition to breast cancer in African American women

Abstract Background: Although the role of BRCA1 and BRCA2 has been well studied in women of European ancestry, the contribution of these and other genes associated with hereditary cancers remains unknown in other populations. Here, we utilized panel testing to analyze 94 cancer predisposition genes in African American women (AAW) diagnosed with invasive breast cancer. Methods: 145 self-described AAW who enrolled in the Clinical Breast Care Project from 2001-2012 and had genomic DNA available were identified. Targeted sequencing was performed using the TruSight Cancer panel (Illumina). Pathogenic mutations were identified using VariantStudio and classified as pathogenic, uncertain significance (VUS), or benign using ClinVar. Results: Mean age at diagnosis was 52.1 years (range 25-81 years), and 32% of AAW had a family history. The majority of tumors were ER+HER2- (53%) followed by triple-negative breast cancer (TNBC, 34%). Seven percent of AAW had pathogenic mutations in high-risk genes including BRCA1 (n=7), BRCA2 (n=3), and TP53 (n=1); VUS were detected in BRCA1 (n=1) and BRCA2 (n=2); and an additional woman had a private variant (D2965E) in BRCA2. A further 1% of AAW harbored mutations in the moderate-penetrance gene CHEK2. VUS were also detected in ATM (n=9), CDH1 (n=1), CHEK2 (n=2), MSH2 (n=1), MSH6 (n=5), NBN (n=1), PALB2 (n=4), PMS2 (n=3), RAD51C (n=1), SMAD4 (n=1), TP53 (n=1), and TSC2 (n=1). Conclusions: Although 94 cancer predisposition genes were evaluated, pathogenic mutations in AAW were detected only in four well-established breast cancer predisposition genes (BRCA1, BRCA2, CHEK2, and TP53). Overall mutation frequency was 9%; however, an additional 25% of AAW harbored private variants and VUS, underscoring the critical need to establish the pathogenicity of these variants. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of the U.S. Government. Citation Format: Heather L. Blackburn, Craig D. Shriver, Rachel E. Ellsworth. Panel testing to evaluate genetic predisposition to breast cancer in African American women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B77.

Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer.

Characterizing moderate penetrance susceptibility genes is an emerging frontier in colorectal cancer (CRC) research. GALNT12 is a strong candidate CRC-susceptibility gene given previous linkage and association studies, and inactivating somatic and germline alleles in CRC patients. Previously, we found rare segregating germline GALNT12 variants in a clinic-based cohort (N=118) with predisposition for CRC. Here, we screened a new population-based cohort of incident CRC cases (N=479) for rare (MAF ≤1%) deleterious germline GALNT12 variants. GALNT12 screening revealed eight rare variants. Two variants were previously described (p.Asp303Asn, p.Arg297Trp), and additionally, we found six other rare variants: five missense (p.His101Gln, p.Ile142Thr, p.Glu239Gln, p.Thr286Met, p.Val290Phe) and one putative splice-altering variant (c.732-8 G>T). Sequencing of population-matched controls (N=400) revealed higher burden of these variants in CRC cases compared with healthy controls (P=0.0381). We then functionally characterized the impact of substitutions on GALNT12 enzyme activity using in vitro-derived peptide substrates. Three of the newly identified GALNT12 missense variants (p.His101Gln, p.Ile142Thr, p.Val290Phe) demonstrated a marked loss (>2-fold reduction) of enzymatic activity compared with wild-type (P≤0.05), whereas p.Glu239Gln exhibited a ∼2-fold reduction in activity (P=0.077). These findings provide strong, independent evidence for the association of GALNT12 defects with CRC-susceptibility; underscoring implications for glycosylation pathway defects in CRC.

Beyond BRCA1/2: Clinician-reported utility 3 years post panel testing.

e18705Background: Germline testing guidelines are centered on BRCA1 and BRCA2 despite clear medical management recommendations in several other high and moderate penetrance genes. Clinician utiliza...

Managing Patient with Mutations in PALB2, CHEK2, or ATM

The use of panel testing of multiple cancer-causing genes has allowed to find a subset of patients with harmful mutations in moderate penetrance genes. While extensive information is available regarding patients with BRCA1 and BRCA2 pathogenic variants, information regarding these less common genes and their management remains scarce. The aim of this review is to discuss penetrance, incidence, and management recommendations for PALB2, ATM, and CHEK2. NCCN guidelines now provide management recommendation for patients with pathogenic variants in these genes. In addition, more widespread testing has provided more information on penetrance and incidence. Although this is a huge step toward improving quality of care, prospective studies are still needed. We summarize the NCCN and other guidelines/suggestions for these genes and deliver our insight on the matter based on the best information we could find. PALB2, ATM, and CHEK2 are less penetrant than BRCA1–2 and have a different spectrum, suggesting differing management. Data about incidence and penetrance along with management recommendations for these genes are provided.

Hereditary Breast and Ovarian Cancer Syndrome: Moving Beyond BRCA1 and BRCA2.

The recent implementation of next generation sequencing and multigene platforms has expanded the spectrum of hereditary breast and ovarian cancer syndrome, beyond the traditional genes BRCA1 and BRCA2. A large number of other moderate penetrance genes have now been uncovered, which also play critical roles in repairing double stranded DNA breaks through the homologous recombination pathway. This review discusses the landmark discoveries of BRCA1 and BRCA2, the homologous repair pathway and new genes discovered in hereditary breast and ovarian cancer syndrome, as well as their clinicopathologic significance and implications for genetic testing. It also highlights the new role of PARP inhibitors in the context of synthetic lethality and prophylactic surgical options.

Abstract ES2-3: Managing increased breast cancer risk based on high and moderate penetrance gene mutations

Abstract Genetic testing in the modern era increasingly examines multiple genes using next generation technologies. Most assays include the high penetrance genes, which confer lifetime breast cancer risk greater than 5-fold, include BRCA1/2, TP53, CDH1 and PALB2. Moderate penetrance genes are associated with lifetime breast cancer risk in the range of 2-3 fold, and include ATM, NF1, CHEK2 (mutation-specific) and NBN, with BARD1 and others potentially joining the group. Substantial data has emerged from studies of women with BRCA1/2 mutations, evaluating the performance of screening technologies, such as mammogram, breast MRI and ultrasound, and the efficacy of risk-reducing breast and ovarian/fallopian tube surgical procedures. Guidelines exist in the NCCN (US) and ESMO guidelines in Europe, among others, trying to provide recommendations for the age at which to initiate screening or undergo risk-reducing salpingo-oophorectomies, for example. Data are increasing on the moderate penetrance genes but there is still much reliance on extrapolation from the high-penetrance genes, which should be done thoughtfully. One approach is to estimate the age at which lifetime breast cancer risk equals the risk from a high penetrance gene when screening is to begin and initiate imaging surveillance at that time. For example, initiation of annual breast imaging would be at age 40 for ATM (RR 2.8) instead of age 25 as is done for BRCA1/2 or age 20 as for TP53. However, there are no data that this is the correct age at which to initiate screening, so this practical suggestion must meet criteria for reasonableness as well as effectiveness. Other source of data may include more precise gene-specific risk estimates from focused genetic epidemiology studies, and ongoing data from studies of prospectively identified mutation carriers. Further understanding of the mechanisms of carcinogenicity for mutation carriers may also help to provide insights that can guide therapeutic and preventive approaches. For example, the work on RANK ligand by Lindeman et al has led to the development of a definitive breast cancer prevention trial examining the RANK-Ligand inhibitor Denosumab in BRCA1 mutation carriers, entitled BRCA-P, being led by C. Singer of the ABCSG and Dr. Lindeman, and to be conducted in sites around the world. Other approaches are in development and will be discussed. Citation Format: Garber JE. Managing increased breast cancer risk based on high and moderate penetrance gene mutations [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES2-3.

Multi-gene Panel Testing in Breast Cancer Management.

Hereditary predisposition accounts for approximately 10% of all breast cancers and is mostly associated with germline mutations in high-penetrance genes encoding for proteins participating in DNA repair through homologous recombination (BRCA1 and BRCA2). With the advent of massive parallel next-generation DNA sequencing, simultaneous analysis of multiple genes with a short turnaround time and at a low cost has become possible. The clinical validity and utility of multi-gene panel testing is getting better characterized as more data on the significance of moderate-penetrance genes are collected from large, cancer genetic testing studies. In this chapter, we attempt to provide a general guide for interpretation of panel gene testing in breast cancer and use of the information obtained for clinical decision-making.