Variants In Cancer Susceptibility Genes Research Articles

Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast.

To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort. Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years. The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

Prevalence and spectrum of germline pathogenic variants in cancer susceptibility genes among mexican patients with exocrine pancreatic cancer

BackgroundAlthough universal germline genetic testing is recommended for patients with exocrine pancreatic cancer (PC), access to genetic testing remains limited in low- and middle-income countries. This study aims to narrow the gap in our understanding of the spectrum of germline pathogenic and likely pathogenic variants (PVs) in cancer susceptibility genes in the Mexican population. MethodsThe landscape of PVs in cancer susceptibility genes was identified by next-generation sequencing multigene panel assays among patients with PC who were enrolled in the Clinical Cancer Genomics Community Research Network prospective registry in Mexico City. ResultsFrom August 2019 to April 2023, 137 patients underwent genetic testing. The median age at diagnosis was 60 years (range 36–85), 58.4 % were women, and 38.7 % were metastatic at diagnosis. The frequency of germline PVs was 16 % (n = 22): ATM 36.4 % (n = 8), CDKN2A/p16INK4A 27.3 % (n = 6), BRCA2 9.1 % (n = 2), PALB2 9.1 % (n = 2), CHEK2 9.1 % (n = 2), TP53 4.5 % (n = 1), and NF1 4.5 % (n = 1). Additionally, 2 carriers of monoallelic germline variants in MUTYH were identified. No significant differences were observed between carriers and non-carriers in terms of family history of pancreatic cancer. ConclusionsWe identified a significant frequency of actionable germline PVs in Mexicans with PC, wherein the majority were in a broad spectrum of genes associated with the homologous recombination DNA repair mechanism. Most pancreatic cancer associated PVs were detected in non-BRCA genes, so our findings support the recommendation of multigene panel testing for genetic cancer risk assessment of Mexican individuals with PC.

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥ 50 years.

e12547 Background: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in ethnically diverse Israeli population. Since 2019 testing for these recurring PVs is reimbursed unselectively for all breast cancer (BC) patients in Israel, while extended multi-gene panel testing is reimbursed based on specific clinical criteria. We aimed to evaluate the yield of genotyping for these recurring PVs in non-Ashkenazi Jewish BC patients diagnosed ≥ 50 years. Methods: Clinical and genotyping data of all BC patients undergoing oncogenetic counseling at the Oncology institute at Sheba medical center from June 2017 to December 2023 were reviewed. Results: Of 2706 BC patients (mean age at diagnosis 54 years; range, 20-92 years) counseled, 515 patients of non-Ashkenazi Jewish (all 4 grandparents) descent, diagnosed ≥ 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) in non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants (not all in BC related genes) were found in 2.5% of genotyped TNBC and in 3.7% of non-TNBC patients, including CHEK2 c.499G>A (n=3), APC c.3920T>A (n=4), and heterozygous MUTYH c.1187G>A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2), ATM c.103C>T (n=2) and NBN (n=1). Conclusions: The observed low rates of PV detection in non-Ashkenazi Jewish non-TNBC cases older than 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥50 years.

Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed. Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n=3), APC c.3920T>A (n=4), and heterozygous MUTYH c.1187G>A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n=2), and NBN c.966C>G (n=1). The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Abstract 6155: Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts

Abstract Background: Increasing evidence suggests germline genetic susceptibility influences the risk of developing subsequent neoplasms (SNs)—a major cause of morbidity and mortality—among childhood cancer survivors, but studies have been hampered by sample size and limited gene sets. We pooled two large-scale cohorts of childhood cancer survivors to characterize overall and specific SN risks among individuals carrying germline variants in 88 known cancer susceptibility genes with an autosomal dominant inheritance pattern. Methods: Using whole-genome or whole-exome sequencing data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort (median [interquartile range] follow-up, 29.7 [13.8] years), we identified rare, potentially protein-damaging germline variants with SnpEff/ClinVar. Conditional logistic regression evaluated overall SN and SN-specific risk, with up to 100 SN-free controls matched to cases by age, sex, primary childhood cancer type, SN type, radiation dose, chemotherapy, study, and follow-up time. Results: Among 11840 individuals (50.6% female) who survived childhood cancer, 2162 (18.3%) developed at least one SN. The risk of developing any SN was elevated among 288 survivors carrying rare, potentially protein-damaging germline variants in an autosomal dominant cancer susceptibility gene (cases=13.3%; controls=9.6%; odds ratio [OR], 1.48; 95% confidence interval [CI], 1.30-1.70; P=5.12x10-5). A similar proportion of carriers was observed among those who developed common SNs such as basal cell carcinoma (N=107/882, 12.1%), meningioma (N=52/373, 13.9%), breast cancer (N=49/353, 13.9%), and thyroid cancer (N=32/243, 13.2%). Higher frequencies of carriers were observed in less common SNs, specifically sarcoma (N=24/151, 15.9%), colorectal cancer (N=15/72, 20.8%), and glioma (N=16/64, 25.0%). The observed associations were generally consistent regardless of treatment type for first primary childhood cancer. Gene-specific analyses revealed that the risk of developing any SN was most pronounced among individuals carrying variants in TP53 (cases=0.6%; controls=0.04%; OR, 9.93; 95% CI, 4.62-21.34; P=0.001) and FANCM (cases=0.9%; controls=0.5%; OR, 2.45; 95% CI, 1.48-4.03; P=0.018). Conclusion: In large-scale cohorts of childhood cancer survivors with long-term follow-up, individuals carrying potentially protein-damaging germline variants in known autosomal dominant cancer susceptibility genes have substantially increased SN risk, emphasizing the importance of genetic testing and consideration of genetic risk in follow-up guidelines. However, these individuals account for a small fraction of all SN cases, warranting future research on underlying risk factors in this population. Citation Format: Shahriar A. Zamani, Danielle M. Karyadi, Stephen W. Hartley, Joshua N. Sampson, Todd Gibson, Peter Kraft, Stephen J. Chanock, Lindsay M. Morton. Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6155.

Abstract 775: Underlying germline genetic architecture of pediatric sarcomas: Evaluating the role of common and rare variants in 4,160 patients

Abstract Some evidence suggests that pediatric sarcomas have both shared and distinct genetic profiles; however, large-scale efforts to characterize germline genetic susceptibility across these malignancies are limited by their rarity. We evaluated the role of common and rare variants in the genetic etiology of the more frequent pediatric sarcomas: osteosarcoma (OS); Ewing sarcoma (ES); and rhabdomyosarcoma (RMS), subcategorized into embryonal (ERMS) and alveolar (ARMS). METHODS: We evaluated 4,161 European-ancestry cases with genotype data (1,843 OS, 733 ES, 1,585 RMS, and ~61,000 cancer-free adult controls) and 2,474 cases with exome or genome sequencing (1,002 OS, 579 ES, 893 RMS, and 1,057 controls; jointly called with the same QC). Analyses included: 1) estimating disease heritability for both common SNPs (MAF>3%; genome-wide) and rare loss-of-function variants (MAF<1%; exome-wide); and 2) determining the frequency of rare predicted pathogenic (P) or likely pathogenic (LP; ACMG-AMP) variants in cancer susceptibility genes (CSG). RESULTS: For OS, we conducted a new GWAS and determined that common variants explained 2.7% (SE 1.1%) of disease heritability, while rare LOF variants explained 12.7% (SE 1.5%; compared to 0.4% for synonymous variants). A similar pattern was observed for ERMS, where rare LOF variants explained a greater proportion of disease heritability (RMS 8.6%, SE 1.2%; ERMS 12.6%, SE 1.7%; ARMS n/a due to small sample size) compared to common variants from our new GWAS (0.9%, SE 1.6%). Conversely, common variants explained a greater proportion of ES heritability (5.4%, SE 0.5%) and of ARMS heritability (15.5%, SE 6.4%). For 113 established CSGs, and for the 60 moderate-to-high penetrant autosomal dominant (AD) genes, OS and ERMS had significantly (Pexact<0.01) more rare P/LP variants overall compared to controls; whereas ARMS and ES had significantly fewer P/LP variants than ERMS and OS, similar to the controls. We confirmed previously reported AD genes, and identified new genes, with an enrichment of P/LP variants in ERMS and OS compared to controls. For both ARMS and ES, the only AD gene significantly enriched for P/LP variants was CHEK2. For all cases, patients with a P/LP variant were significantly younger and had significantly more poor outcomes (ie, metastasis, stage 4 disease, and/or death) than those without. For 49 autosomal recessive CSGs, heterozygous P/LP carrier frequencies were similar among all sarcomas (8-11%), and several specific genes had similar P/LP variant enrichment across sarcomas, and for ES and ARMS only, compared to controls. CONCLUSION: In the largest set of pediatric sarcoma cases assembled to date, genetic susceptibility was largely driven by rare P/LP AD gene variants in tumor types not characterized by canonical somatic fusions (OS and ERMS). In contrast, fusion-driven tumor types (ES and ARMS) were driven more by common variants. Citation Format: Lisa Mirabello, Laura E. Egolf, Bin Zhu, D. Matthew Gianferante, Kevin Wang, Shengchao Alfred Li, Mitchell J. Machiela, Logan G. Spector, Joshua D. Schiffman, Aniko Sabo, Alexander Renwick, Bailey Martin-Giacalone, Michael E. Scheurer, Sharon Plon, Douglas Hawkins, Rajkumar Venkatramani, Douglas Stewart, Lindsay M. Morton, Melissa M. Hudson, Gregory T. Armstrong, Smita Bhatia, Michael Dean, Katherine A. Janeway, Ana Patiño-Garcia, Fernando Lecanda, Massimo Serra, Claudia Hattinger, Katia Scotlandi, Adrienne M. Flanagan, Fernanda Amary, Irene L. Andrulis, Jay S. Wunder, Mandy L. Ballinger, David M. Thomas, Olivier Delattre, Aubrey K. Hubbard, Jia Liu, Wen Luo, Belynda D. Hicks, Meredith Yeager, Maryam Rafati, Wen-Yi Huang, Maria T. Landi, Adriana Lori, Ryan Diver, Sharon A. Savage, Stephen J. Chanock, Philip J. Lupo. Underlying germline genetic architecture of pediatric sarcomas: Evaluating the role of common and rare variants in 4,160 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 775.

Two Germline Pathogenic Variants in Cancer Susceptibility Genes and Their Null Implication in Breast Cancer Pathogenesis: The Importance of Tumoral Homologous Recombination Deficiency Testing.

Homologous recombination proficiency in patients with breast cancer despite germline PALB2/RAD51C pathogenic variants.

Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes

PurposeAs panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes. MethodsA retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene. ResultsAmong 644 individuals with DPVs, combinations that included the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with ATM+CHEK2 (43), compared with ATM (47, P = .016) or CHEK2 (47, P = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the ATM+CHEK2 with single-gene controls. Individuals with 2 CHEK2 PVs also were younger at first cancer diagnosis (40) compared with single CHEK2 PV controls (47, P = .0038). This difference was not driven by age at first BC diagnosis among females. ConclusionIndividuals with ATM+CHEK2 or 2 CHEK2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations.

Exome Sequencing Reveals Novel Germline Variants in Breast Cancer Patients in the Southernmost Region of Thailand.

Germline carriers of pathogenic variants in cancer susceptibility genes are at an increased risk of breast cancer (BC). We characterized germline variants in a cohort of 151 patients diagnosed with epithelial BC in the southernmost region of Thailand, where the predominant ethnicity differs from that of the rest of the country. Whole exome sequencing was used to identify and subsequently filter variants present in 26 genes known to be associated with cancer predisposition. Of the 151 individuals assessed, 23, corresponding to 15.2% of the sample, exhibited the presence of one or more pathogenic or likely pathogenic variants associated with BC susceptibility. We identified novel germline truncating variants in BRIP1, CHEK2, MSH6, PALB2, and PTEN and annotated variants of uncertain significance (VUSs), both novel and previously documented. Therefore, it is advisable to use genetic testing as an additional risk screening method for BC in this area.

Pathogenic germline variants in BRCA1 and TP53 increase lung cancer risk in Chinese.

Multiple studies have identified pathogenic germline variants in cancer susceptibility genes (CSGs) in Chinese lung cancer patients; however, accurate assessment of these variants' contributions to cancer predisposition is always hampered by the absence of data on the prevalence of these variants in the general population. It is necessary to conduct a large-scale case-control study to identify CSGs that significantly increase the risk of lung cancer. We performed targeted sequencing of a CSGs panel in 1117 lung cancer patients and 16,327 controls from the general Chinese population. In comparison to controls, lung cancer patients had a considerably higher prevalence of pathogenic and likely pathogenic (P/LP) variations. Among lung cancer patients, 72% of P/LP variants carriers did not have a family cancer history, who would be ignored if germline testing was only provided for patients meeting family history-based criteria. Furthermore, compared to individuals with late-onset lung cancer, patients with early-onset lung cancer had a considerably higher prevalence of P/LP variations. With odds ratios (ORs) ranging from 4-fold (BRCA1: OR, 4.193; 95%CI, 1.382-10.768) to 29-fold (TP53: OR, 29.281; 95%CI, 1.523-1705.506), P/LP variants in the BRCA1 and TP53 genes were discovered to be strongly related to increased lung cancer risk. Additionally, with ORs ranging from 7.322-fold to infinity, we discovered 23 variations previously categorized as non-P/LP variants were highly enriched in lung cancer patients. Our findings indicated that P/LP variants in BRCA1 and TP53 conferred increased risk of lung cancer in Chinese.

Genetic testing in patients with pancreatic cancer to reveal pathogenic variants in cancer susceptibility genes.

e16276 Background: Pancreatic cancer is one of the most fatal malignancies. It accounts for 2% of all cancers and 5% of cancer-related deaths. Hence, it is essential to identify pancreatic cancer at an earlier stage to improve outcomes. A variety of hereditary cancer syndromes have been associated with an increased risk of developing pancreatic cancer, and these individuals may benefit from surveillance plans. PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring germline variant in the Homologous recombination repair (HRR) genes. Our aim was to determine the prevalence of germline pathogenic/likely pathogenic variants in cancer predisposing genes in patients with pancreatic cancer. Methods: In total, 113 patients diagnosed with pancreatic cancer were referred to our laboratory for genetic testing. The analysis of 52 genes involved in hereditary cancer predisposition was performed using a NGS approach. Results: A germline pathogenic/likely pathogenic variant was identified in 20% of patients analyzed. Among individuals with germline pathogenic/likely pathogenic variants, 60% had a positive finding in a pancreatic cancer susceptibility gene; ATM (20%), BRCA1 (20%), BRCA2 (12%), CDKN2A (4%), PALB2 (4%) while 40% carried positive findings in other cancer susceptibility genes. More specifically, in CHEK2 (16%), MRE11 (4%), RAD50 (4%), RAD51C (4%), MUTYH (8%) and NTLH1 (4%). Notably, 84% of pathogenic variants were identified in genes associated with the HRR pathway ( ATM, BRCA1, BRCA2, CHEK2, MRE11, PALB2, RAD50 and RAD51C). Conclusions: Our results indicate that multigene genetic testing is meaningful for pancreatic cancer patients as in 20% of tested individuals we identified findings associated with pancreatic or other cancer predisposition. Moreover, pathogenic/likely pathogenic variants in HRR genes, were identified in 16.6% patients and these patients might benefit from targeted treatments, such as PARP inhibitors or platinum-based treatment.

Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.

e16551 Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.

The Impact of Germline Alterations in Appendiceal Adenocarcinoma.

More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable. Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.

Lynch syndrome: influence of additional susceptibility variants on cancer risk.

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.

Abstract P6-02-15: Don’t get lost in translation: Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) recommendations for reporting germline cancer susceptibility gene variants in 19 languages – breast cancer as a model

Abstract Genetic testing for cancer susceptibility is a cornerstone of precision cancer prevention and care. Major communication hurdles remain for the differently specialized professionals involved in the identification, counselling, and clinical management of at-risk individuals. This may be ascribed to gaps in the genetic/genomic literacy of health care providers and to an ambiguous lexicon used for variant description. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium endorses controlled terminology and a framework for interpretation and reporting of germline variants in cancer susceptibility genes (PMID: 30962250). However, for most ENIGMA affiliates a language other than English is used for written and verbal communication of genetic test results, potentially confounding local application of the published framework. The ENIGMA Clinical Working Group thus launched a Vocabulary Translation Project (VTP) to translate the ENIGMA recommendations into the various languages spoken by the membership. The VTP involved 65 ENIGMA members from 22 countries organized into 19 language-specific teams, covering Catalan, Chinese, Czech, Danish, Dutch, Finnish, French, Galician, German, Greek, Italian, Japanese, Malay, Norwegian, Polish, Portuguese, Spanish (Castilian), Swedish, and Tagalog. Excerpts from the original publication were selected for translation based on a majority consensus and included a glossary of terms and recommendations for interpreting and reporting germline sequence variants in (breast) cancer susceptibility genes. Using a two-step process, each team conducted the relevant translation followed by independent back-translation to English. The VTP proved useful to reappraise the reference text. It disclosed transnational issues, which prompted revision of the original source to emphasize that risk estimates and actionability were based on breast cancer as an exemplar. It also highlighted country-specific differences with regards to breast cancer risk assessment (e.g. different absolute/relative breast cancer risk cut points) and management. As a secondary outcome, via electronic survey of the participating teams we documented the perceived high value of the translation effort and its expected positive impact on more consistent clinical management of carrier individuals. The identified target audience encompasses medical geneticists, physicians of other specialties participating in multidisciplinary teams, genetic counselors, primary care physicians, as well as non-health care professionals, e.g. journalists and science communicators. The outreach program includes dissemination of the translations via local, regional, and especially national networks and their use for education and training purposes. Because French, Portuguese, and Spanish are widely used as official, co-official, or secondary languages, the reach of the VTP potentially extends to a greater number of countries and territories, mostly in Central and South America, Caribbean, and Africa. By moving a step forward towards terminological coherence across disciplines and borders, we will facilitate more precise delivery and clinical application of genetic test results for breast cancer predisposition. Our translated recommendations will improve interdisciplinary cross-talk and carriers’ awareness of the risks and implications associated with their status, contributing to more informed decision-making. We used breast cancer as a blueprint. Application of the model to other cancer types will require calibration on the cancer-specific absolute and relative risks. Citation Format: Arcangela De Nicolo, Diana M. Eccles, Sarah Louise Ariansen, Michela Biancolella, Miguel de la Hoya, Orland Diez, Hans Ehrencrona, Florentia Fostira, Tiara Hassan, Issei Imoto, Artur Kowalik, Fabienne Lesueur, Arjen R. Mensenkamp, Heli Nevanlinna, Joanne Ngeow, Edenir I. Palmero, Inge Søkilde Pedersen, Frances Que, Jana Soukupová, Yen Tan, Ana Vega, Amanda B. Spurdle, Paolo Radice. Don’t get lost in translation: Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) recommendations for reporting germline cancer susceptibility gene variants in 19 languages – breast cancer as a model [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-15.

Racial/ethnic differences of germline pathogenic variants in cancer susceptibility genes among patients with early-onset colorectal cancer.

19 Background: The burden of early-onset colorectal cancer (CRC diagnosed before age 50 years) differs across racial/ethnic groups. Yet the distinct prevalence and spectrum of germline pathogenic variants associated with early-onset CRC by race/ethnicity is uncharacterized. Methods: We identified 3,980 early-onset CRC patients unselected for family CRC history who underwent clinical multi-gene panel testing of 14 CRC susceptibility genes ( MLH1, MSH2, MSH6, PMS2, SMAD4, APC, BMPR1, CHEK2, EPCAM, MUTYH, PTEN, STK11, CDH1, and TP53) performed by a nationwide clinical testing laboratory from 2012 to 2016 and identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White. Multi-gene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. Clinical and individual/family histories were ascertained from clinician-completed test requisition forms. Germline variant prevalence and spectrum in early-onset CRC was determined by race/ethnicity. Pathogenic variant comparisons by race/ethnicity were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site and sequence. Results: Among 3,980 early-onset CRC patients, a total of 503 germline genetic variants were identified in 481 individuals (12.1%). By race/ethnicity, 12.7% of Ashkenazi Jewish, 8.6% of Asian, 10.3% of Black, 14.0% of Hispanic, and 12.3% of White individuals presented with a pathogenic variant in a CRC susceptibility gene. Nearly 7% of early-onset CRC patients (n = 268) presented with a germline pathogenic mutation in a mismatch repair gene—with the prevalence of Lynch Syndrome in early-onset CRC differing across racial/ethnic groups ( P= 0.037). The prevalence of germline APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants also varied by race/ethnicity (all P< 0.02). Overall, Asian individuals with early-onset CRC had 49% lower odds of carrying a pathogenic germline variant in a CRC susceptibility gene versus White individuals in adjusted models (Odds Ratio [OR] = 0.51, 95% Confidence Interval [CI]: 0.26-0.99, P= 0.046). Ashkenazim and Hispanic individuals had higher odds of presenting with pathogenic APC and MLH1 variants, respectively, compared with White individuals in adjusted models ( APC: OR = 8.69, 95% CI: 2.68-28.21, P= 0.0003; MLH1: OR = 2.67, 95% CI: 1.30-5.49, P= 0.007). Conclusions: Of 3,980 patients with early-onset CRC unselected for family history, the prevalence and spectrum of pathogenic germline variants differed across racial/ethnic populations. Beyond multigene panel testing for all early-onset CRC patients, further study is needed to optimize genes selected for germline genetic testing in early-onset CRC across diverse groups—which would have clinical implications for disease surveillance and intervention.

Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence

BackgroundBOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future...

Collaboration to Promote Research and Improve Clinical Care in the Evolving Field of Childhood Cancer Predisposition.

Germline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affected children requires distinct considerations given the early onset of cancers, lifelong risks of additional cancers, and potential late effects of therapy. Herein, we discuss efforts to leverage existing infrastructure, organize experts, and develop a new consortium to optimize care and advance research for children with CPS. A 2016 workshop organized by the American Association for Cancer Research united many experts in childhood cancer predisposition and resulted in publication of multiple consensus guidelines for tumor surveillance. More recently, several of these authors established the Consortium for Childhood Cancer Predisposition (C3P), a multi-institutional collaboration that provides a structure for systematic research in cancer predisposition, screening, and prevention in children. The Consortium intends to work with other cooperative groups to merge longitudinal data from children with CPS throughout the continuum of the cancer risk period, as well as cancer treatment and survivorship care, to optimize overall outcomes.

Germline Aberrations in Pancreatic Cancer: Implications for Clinical Care.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis and represents a major public health issue, as both its incidence and mortality are expecting to increase steeply over the next years. Effective screening strategies are lacking, and most patients are diagnosed with unresectable disease precluding the only chance of cure. Therapeutic options for advanced disease are limited, and the treatment paradigm is still based on chemotherapy, with a few rare exceptions to targeted therapies. Germline variants in cancer susceptibility genes—particularly those involved in mechanisms of DNA repair—are emerging as promising targets for PDAC treatment and prevention. Hereditary PDAC is part of the spectrum of several syndromic disorders, and germline testing of PDAC patients has relevant implications for broad cancer prevention. Germline aberrations in BRCA1 and BRCA2 genes are predictive biomarkers of response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib and platinum-based chemotherapy in PDAC, while mutations in mismatch repair genes identify patients suitable for immune checkpoint inhibitors. This review provides a timely and comprehensive overview of germline aberrations in PDAC and their implications for clinical care. It also discusses the need for optimal approaches to better select patients for PARP inhibitor therapy, novel therapeutic opportunities under clinical investigation, and preclinical models for cancer susceptibility and drug discovery.

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), range: 13–88 years; 64% male], 85 participants [6.4%; 95% CI (5.1, 7.8)] had one or more P/LP germline variant in a wider range of CSGs than previously recognized. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield, we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.