A unique case of two somatic APC mutations in an early onset cribriform-morular variant of papillary thyroid carcinoma and overview of the literature Abstract We report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is highly suggestive for familial adenomatous polyposis (FAP), there was no family history of FAP. In the tumor biallelic, inactivating APC variants were identified. The patient tested negative for germline variants based on analysis of genomic DNA from peripheral blood leukocytes. Somatic mosaicism was excluded by subsequent deep sequencing of leukocyte and normal thyroid DNA using next generation sequencing (NGS). This report presents a rare sporadic case of CMV-PTC, and to the best of our knowledge the first featuring two somatic APC mutations underlying the disease, with an overview of CMV-PTC cases with detected APC and CTNNB1 pathogenic variants from the literature.

Should unaffected female BRCA2 pathogenic variant carriers be told there is little or no advantage from risk reducing mastectomy?

TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling Abstract Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.

Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery Abstract Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.

Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history Abstract Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54–4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.

Health behaviours and beliefs in individuals with familial pancreatic cancer Abstract Individuals at high risk for pancreatic cancer are recommended surveillance and healthy lifestyle behaviours and patient experience with recommendations are understudied. To describe engagement and experience with surveillance, tobacco and alcohol use, health beliefs and motivation (Champion Health Belief Measure) and the relationship with personal, psychosocial (Impact of Event Scale), and familial characteristics. Interest in integrative therapies (complementary therapies) are described. A multi-site cross-sectional survey including individuals at high risk for pancreatic cancer with no diagnosis of pancreatic cancer who have been evaluated at a comprehensive cancer center. Descriptive statistics and Wilcoxon rank sum test and Fisher’s exact test were used to assess univariate associations. Of the 132 respondents (72% response rate), 92 (70%) reported undergoing surveillance which was associated with older age (p = 0.001). Of which, 36% and 51% report that magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS), respectively, were uncomfortable; 22% and 30% dread the next MRI or EUS, respectively. Of those who reported alcohol consumption (n = 88); 15% consumed 1 or more drinks daily and no alcohol consumption was associated with higher Impact of Event scale scores (p = 0.024). A total of six participants were currently smoking every day or some days. Participants reported high motivation to engage in heathy behaviours and 92% were interested in integrative therapies. In these select participants, most were engaging in pancreatic cancer surveillance, alcohol intake was moderate, and tobacco intake was minimal. Modifiable factors, such as experience and comfort with surveillance could be addressed. The sample is motivated to engage in behavioural health intervention.

Lynch syndrome with exclusive skin involvement: time to consider a molecular definition? Abstract Muir–Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 76 years-old male patient heterozygous for a pathogenic MSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunohistochemical loss of MSH2 and MSH6 expression. There was no apparent family history of neoplasia. Based on the variable involvement of the skin and internal organs, we suggest that the definition of tumor associations that are often observed as variants of inherited tumor syndromes, such as MTS, should be guided by the underlying molecular bases. In addition, the presence of multiple sebaceous tumors, especially if showing MMR deficiency, appears to be a very strong indicator of a constitutional MMR gene defect. The reasons underlying the high phenotypic variability of cutaneous phenotypes associated with constitutional MMR defects are yet to be determined.

Population frequencies of pathogenic alleles of BRCA1 and BRCA2 : analysis of 173 Danish breast cancer pedigrees using the BOADICEA model Abstract The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant in BRCA1 or BRCA2 based on her pedigree and the population frequencies of pathogenic alleles of BRCA1 (0.0006394) and BRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles of BRCA1 and BRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well between carriers and non-carriers of pathogenic variants (area under the receiver operating characteristics curve: 0.81; 95% CI 0.74–0.86) but underestimated the frequency of carriers of pathogenic variants in BRCA1 or BRCA2 as measured by the observed-to-expected ratio (O/E 1.83; 95% CI 1.18–2.84). This reflects findings from older studies of BOADICEA in UK, German, Italian, and Chinese populations, all accounting for the different calibration for different carrier probabilities. To improve the performance of BOADICEA for non-UK populations, we developed a method to derive population frequencies of pathogenic alleles of BRCA1 and BRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher for BRCA1 (0.0015; 95% CI 0.00064–0.0034) and lower for BRCA2 (0.00052; 95% CI 0.00018–0.0017) after adjusting for the different calibration of BOADICEA for different carrier probabilities. Incorporating additional population frequencies into BOADICEA could improve its performance for non-UK populations.

Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers Abstract Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15–20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients’ surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR − 0.703 [95% CI − 1.201 to − 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined.

Inequities in multi-gene hereditary cancer testing: lower diagnostic yield and higher VUS rate in individuals who identify as Hispanic, African or Asian and Pacific Islander as compared to European Abstract The identification of germline pathogenic/likely pathogenic (P/LP) variants in cancer predisposition genes can guide treatment and management decisions for the individual being tested and potentially at-risk relatives. Prior studies have raised concerns of racial/ethnic disparities in the detection rates of P/LP variants and variants of uncertain significance (VUSs). In 2018, Color Genomics™, a commercial laboratory, made de-identified, aggregate genetic and clinical information from 50,000 individuals who completed testing for 30 cancer predisposition genes publicly available. It is the largest publicly available database of its kind from a single laboratory. An analysis of individuals from this database with a negative personal history of cancer that identify as European (n = 31,920), Hispanic (n = 1700), African (n = 462) or Asian and Pacific Islander (n = 2602), demonstrated that the VUS rate in the hereditary breast and ovarian cancer syndrome and Lynch syndrome genes was higher for all non-European groups as compared to the European group; Hispanic (7.1% vs. 5.8%; p = 0.029), African (12.3% vs. 5.8%; p < 0.001), Asian and Pacific Islander (13.1% vs. 5.8%; p < 0.001). In the other cancer genes (OCGs), the P/LP rate was lower; Hispanic (5.1% vs. 7.6%; p < 0.001), African (2.4% vs. 7.6%; p < 0.001), and Asian and Pacific Islander (4.3% vs. 7.6%; p < 0.001). The VUS rate was also higher in the OCGs; Hispanic (16.2% vs. 12.2%; p < 0.001), African (21.6% vs. 12.2%; p < 0.001), Asian and Pacific Islander (24.4% vs. 12.2%; p < 0.001). Our study emphasizes the reality of disparities in the results of cancer genetic testing and highlights factors that propagate these inequities.