Low-penetrance Genes Research Articles

MED12 Loss-of-Function Variants as a Cause of Congenital Diaphragmatic Hernia in Females With Hardikar Syndrome and Nonspecific Intellectual Disability.

Mediator complex subunit 12 (MED12) is required for the assembly of the kinase module of Mediator, a regulatory complex that controls the formation of the RNA polymerase II-mediated preinitiation complex. MED12-related disorders display unique gender-specific genotype-phenotype associations and include X-linked recessive Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants, and X-linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense/frameshift and nonsense/missense variants, respectively. MED12 was previously identified as a low-penetrance candidate gene for non-isolated congenital diaphragmatic hernia (CDH+). At the time, however, there was insufficient evidence to confirm this association. In a clinical database search, we identified 18 individuals who were molecularly diagnosed with MED12-related disorders by exome or genome sequencing, including eight missense, four frameshift, two nonsense, and one splice variant. Nine of these variants have not been previously reported. Two females with nonspecific intellectual disability were found to carry a de novo frameshift variant, indicating that potentially truncating variants causing nonspecific intellectual disability are not limited to nonsense variants. Notably, CDH was reported in three out of seven females with Hardikar syndrome or nonspecific intellectual disability but was not reported in males with MED12-related disorders. These results suggest that pathogenic MED12 variants are a cause of CDH+ in females with Hardikar syndrome and nonspecific intellectual disability.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.

Unveiling the genetic landscape of hereditary melanoma: From susceptibility to surveillance

The multifactorial etiology underlying melanoma development involves an array of genetic, phenotypic, and environmental factors. Genetic predisposition for melanoma is further influenced by the complex interplay between high-, medium-, and low-penetrance genes, each contributing to varying degrees of susceptibility. Within this network, high-penetrance genes, including CDKN2A, CDK4, BAP1, and POT1, are linked to a pronounced risk for disease, whereas medium- and low-penetrance genes, such as MC1R, MITF, and others, contribute only moderately to melanoma risk. Notably, these genetic factors not only heighten the risk of melanoma but may also increase susceptibility towards internal malignancies, such as pancreatic cancer, renal cell cancer, or neural tumors. Genetic testing and counseling hold paramount importance in the clinical context of suspected hereditary melanoma, facilitating risk assessment, personalized surveillance strategies, and informed decision-making. As our understanding of the genomic landscape deepens, this review paper aims to comprehensively summarize the genetic underpinnings of hereditary melanoma, as well as current screening and management strategies for the disease.

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Familial Mediterranean fever and microRNAs.

Familial Mediterranean fever (FMF) is an inherited disorder caused by the gain of function mutations in MEFV (MEditerranean FeVer) gene loci. FMF affects more than 100,000 people worldwide and generally seen in the eastern Mediterranean region and causes the lifelong diseases which have a significant effect on the patient's life quality and health systems. The identification of low penetrant or heterozygous MEFV gene mutations in clinically diagnosed FMF patients was considered that epigenetic or environmental factors may display a role in FMF pathogenesis. Epigenetics might be defined as heritable changes that affect gene expression without any changes in the genome. MicroRNAs (miRNAs) are the main group of small noncoding RNAs, and an important element of epigenetic mechanisms and their discoveries revolutionized our knowledge about biological processes, such as malignant, infectious and autoimmune mechanisms, and contributed to the development of the epigenetic areas. In this review, the studies focusing on the roles of miRNAs in FMF pathogenesis in the last decades were examined and the importance of miRNAs as therapeutic agents which are promising for diagnosis and treatment was discussed.

Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.

Germline variants in BRCA1 and BRCA2 (BRCA1/2) genes are the most common cause of hereditary breast cancer. However, a significant number of cases are not linked to these two genes and additional high-, moderate- and low-penetrance genes have been identified in breast cancer. The advent of next-generation sequencing (NGS) allowed simultaneous sequencing of multiple cancer-susceptibility genes and prompted research in this field. So far, cancer-predisposition genes other than BRCA1/2 have not been studied in the population of Bahrain. We performed a targeted NGS using a multi-panel covering 180 genes associated with cancer predisposition to investigate the spectrum and frequency of germline variants in 54 women with a positive personal and/or family history of breast cancer. Sequencing analysis revealed germline variants in 29 (53.7%) patients. Five pathogenic/likely pathogenic variants in four DNA repair pathway-related genes were identified in five unrelated patients (9.3%). Two BRCA1 variants, namely the missense variant c.287A>G (p.Asp96Gly) and the truncating variant c.1066C>T (p.Gln356Ter), were detected in two patients (3.7%). Three variants in non-BRCA1/2 genes were detected in three patients (1.85% each) with a strong family history of breast cancer. These included a monoallelic missense variant c.1187G>A (p.Gly396Asp) in MUTYH gene, and two truncating variants namely c.3343C>T (p.Arg1115Ter) in MLH3 gene and c.1826G>A (p.Trp609Ter) in PMS1 gene. Other variants of uncertain significance (VUS) were also detected, and some of them were found together with the deleterious variants. In this first application of NGS-based multigene testing in Bahraini women with breast cancer, we show that multigene testing can yield additional genomic information on low-penetrance genes, although the clinical significance of these genes has not been fully appreciated yet. Our findings also provide valuable epidemiological information for future studies and highlight the importance of genetic testing, and an NGS-based multigene analysis may be applied supplementary to traditional genetic counseling.

Association of RAD51, XRCC1, XRCC2, and XRCC3 Polymorphisms with Risk of Breast Cancer.

Background: DNA repair genes are among the low-penetrance genes implicated in breast cancer. However variants of DNA repair genes may alter their protein function thus leading to carcinogenesis. Breast cancer is the most common cancer among women in India. The aim of the present study was to identify association, if any, of single nucleotide polymorphisms (SNP's) in four genes involved in DNA repair pathways including, RAD51 rs1801320, XRCC1 rs25487, XRCC2 rs3218536, and XRCC3 rs861539 with the risk of breast cancer. Materials and Methods: In this case-control study 611 female subjects (311 breast cancer patients and 300 healthy controls) were screened for four SNPs using polymerase chain reaction-restriction fragment length polymorphism analyses. Multifactor dimensionality reduction (MDR) analysis was performed to estimate the gene-gene interaction. Protein-protein interaction network analysis were studied using the STRING database. Results: The GC genotype (p = 0.018) and the combined GC+CC (p = 0.03) genotypes of RAD51 rs1801320 were significantly associated with reduced risk of breast cancer. The CT genotype (p = 0.0001), the combined CT+TT genotypes (p = 0.0002), and the T allele (p = 0.0019) of XRCC3 rs861539 polymorphism were associated with reduced risk of the breast cancer. No association of XRCC1 rs25487 and XRCC2 rs3218536 polymorphisms with breast cancer was observed. MDR analysis indicated a positive interaction between XRCC3 and XRCC2. String network analysis showed that the RAD51, XRCC1, XRCC2, and XRCC3 proteins are in strong interaction with each other and other breast cancer-related proteins such as BRCA2. Conclusion: RAD51 rs1801320 and XRCC3 rs861539 polymorphisms were associated with reduced risk of breast cancer. There is evidence of positive interactions among XRCC1, XRCC2, XRCC3, and RAD51.

Prevalence of unexpected actionable germline pathogenic variants identified on broad-based multi-gene panel testing in a cohort of cancer patients.

10523 Background: Broad-based germline multi-gene panel testing (MGPT) for inherited predisposition has become increasingly common for cancer patients. Both indications for germline testing and the spectrum of genes on MGPT have expanded. We sought to examine the frequency of an unexpected pathogenic/likely pathogenic variant (P/LPV) in patients with a variety of solid and hematologic malignancies undergoing MGPT. Methods: A retrospective review of patients with a history of cancer who underwent MGPT at a single institution from 2015 to 2021 with MGPT of &gt; 20 cancer predisposition genes. Low penetrance genes and genes with a recessive inheritance pattern were excluded. Deidentified pedigrees were analyzed by genetic counselors for clinical diagnostic criteria and gene-specific national testing guidelines to determine whether clinical suspicion of the P/LPV was present. Results: 10,975 cancer patients underwent MGPT. 1,180 (10.9%) patients were found to have &gt; 1 P/LPV in a moderate or highly penetrant cancer susceptibility gene. 357 (3.3%) of the P/LPV were unexpected based on patient’s personal cancer history alone. 208 (1.9%) of the P/LPV remained unexpected after patient and family cancer histories were considered. Most common cancer subtypes with an unexpected P/LPV were breast [1.5% (83/5691)], prostate [2.1% (28/1300)], colorectal [2.2% (18/823)], ovarian/fallopian [1.7% (13/781)] and uterine [ 2.8% (10/352)] cancer. Most frequent unexpected P/LPV were PMS2 (n = 19), MITF (n = 18), ATM (n = 18), BRIP1 (n = 17), CHEK2 (n = 14), HOXB13 (n = 13), SDHA (n = 12), BRCA2 (n = 7), MSH6 (n = 7), SDHC (n = 7), TP53 (n = 7), and PALB2 (n = 6). No predictor of having an unexpected P/LPV was identified in multivariable logistic regression analysis. Low penetrance or recessive variants were found in 521 (4.8%) patients. Variants of uncertain significance (VUS) were found in 3,774 (35.0%) patients. Conclusions: This large retrospective analysis of cancer patients undergoing MGPT identified an overall rate of 1.9% of P/LPV in actionable cancer predisposition genes. Findings were more often unexpected (3.3%) when considering only the patient cancer history, endorsing the importance of family cancer history for consideration of more targeted genetic testing. Identification of moderate or highly penetrant P/LPV in cancer patients is increasingly important in guiding treatment decisions, cancer screening in survivors and testing of at-risk family members. These findings may justify consideration of broader MGPT panels especially when family cancer history is uncertain or unavailable. MGPT also detected a high rate of VUS, reinforcing the importance of physician education to ensure appropriate interpretation and management.

Effect of somatic-germline genomic integration on the contribution of pathogenic germline genetic variants (gPV) to colorectal cancer (CRC) carcinogenesis.

10595 Background: Approximately 14% of CRC patients harbor a germline pathogenic variant (gPV) in a cancer susceptibility gene. As gPV prevalence alone is insufficient evidence for cancer causation, we performed an integrated germline and somatic genomic analysis to discover the extent to which gPVs may be driving CRC carcinogenesis. Methods: Using the MSKCC IMPACT dataset, we identified all patients with CRC who had undergone targeted tumor-normal sequencing (NCT01775072) inclusive of up to 90-genes assessed for germline variants. gPV in tested genes were categorized according to known association with CRC susceptibility and penetrance level. For example, high/moderate penetrance CRC-risk genes included: APC, MLH1, MSH2, MSH6, PMS2, EPCAM, biallelic MUTYH, SMAD4, STK11, BMPR1A, PTEN, POLD1, POLE, TP53. Low-penetrance CRC-risk genes included: monoallelic MUTYH, APC I1307K, CHEK2, BLM. In patients with a gPV, biallelic inactivation at the implicated germline region was inferred based on loss of heterozygosity (LOH) or somatic pathogenic alteration in the tumor. Results: Of 3988 CRC patients, 16.3% (650/3988) harbored at least one gPV (65 patients: 2 gPVs; 3 patients: 3 gPVs). Among a total of 721 gPVs encompassing 55 genes (252 high-penetrance, 118 moderate-penetrance, 351 low/recessive/uncertain-penetrance), overall biallelic inactivation was observed in 41%. In patients with gPVs associated with high/moderate penetrance CRC-risk genes, biallelic inactivation in tumors was present in 70%, while in patients with gPVs in high/moderate penetrance non-CRC genes this was 24% (p = &lt; 0.0001). When assessed according to age at CRC diagnosis, biallelic inactivation in high/moderate penetrance CRC-risk genes was higher in patients diagnosed at age &lt; 35 than in patients age &gt; 50 (p = 0.003); no such difference was observed in high/moderate penetrance non-CRC-risk genes. Among non-CRC-risk genes, in the high/moderate penetrance HRD genes, biallelic loss in the tumor was seen in 29% gATM, 54% gBRCA1, 22% gBRCA2, 30% gBRIP1, and 40% of gRAD51C/D positive patients. There was no difference in the rate of biallelic loss by age in patients with gPVs in HRD genes. Biallelic inactivation in tumors in patients with low-penetrance CRC-risk gPVs was 40% versus 14% in patients with low-penetrance non—CRC gPVs (p = &lt; 0.0001). Conclusions: Germline-somatic integration implicated nearly half of all identified gPVs in CRC carcinogenesis. While the highest rate of biallelic inactivation was seen in high/moderate penetrance CRC-risk genes, biallelic inactivation in non-CRC genes, such as the HRD genes, warrants further assessment to discern the contribution of these gPVs to CRC carcinogenesis. Our findings may have implications for novel treatment strategies exploiting these pathways.

Abstract 1938: Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women

Abstract Abstract Background: Mutations in hereditary breast cancer genes play an essential role in cancer risk. Little is known of the type and frequency of mutations in Hispanic populations in the United States and Central American countries, including Guatemala. Methods: We used exome sequencing to identify mutations in blood DNA from unselected Hispanic breast cancer cases from community recruitment and from two hospitals each in Texas and Guatemala. Data from a structured questionnaire was used to compare mutation carriers of medium and high penetrance genes. Variants were annotated with ClinVar and VarSome. Results: We recruited 262 Hispanic US women, 37 (14%) from community-based recruitment and 225 (86%) from hospitals in Texas. In addition, we ascertained 633 patients from two hospitals in Guatemala City. A total of 91 out of 895 subjects (10%) had a variant classified as pathogenic in a gene with known high or medium penetrance for inherited breast cancer. The most frequently mutated genes were the high penetrance BRCA1 (44/895, 4.9%) followed by BRCA2 (23/895, 2.6%), PALB2 (5/895, 0.6%), CHEK2 (5/895 0.6%), ATM (6/895, 0.7%) and TP53 (6/895, 0.7%). Pathogenic variants were also detected in the moderate penetrance genes BARD1 and MSH6, and rare pathogenic variants detected in the low penetrance genes AXIN2, FH, MLH1, MSH2, MUTYH, NF1, and SDHB. The high ratio of BRCA1/BRCA2 mutations is due to the presence of two potential founder mutations, BRCA1 c.212+1G&amp;gt;A splice mutation (18 cases) and BRCA1 c.799delT (9 cases) in Guatemala. Compared to all others, cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs. 52 years, P&amp;lt;0.001) and were more likely to have a diagnosis before menopause. A higher percentage of mutation carriers had a relative with any cancer (51% vs. 37%, P=0.038) or breast cancer (33% vs. 15%, P&amp;lt;0.001). Patients with pathogenic mutations had a significantly higher percentage of triple-negative disease (60% vs. 13%, P=0.00046). Finally, mammography usage was less frequent in women with a lower socioeconomic status, indicating that this group is less likely to be screened for breast cancer (P&amp;lt;0.001). Conclusions: Guatemalan women have rates of hereditary breast cancer mutations like other populations, and these women are more likely to have early age at diagnosis, triple-negative disease, and family history. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Hispanic women. Citation Format: Jesica Godinez Paredes, Isabel Rodriguez, Megan Ren, Anali Orozco, Jeremy Ortiz, Anaseidy Albanez, Catherine Jones, Zeina Nahleh, Lilian Barreda, Lisa Garland, Dongjing Wu, Jiahui Wang, Victor Argueta, Roberto Orozco, Eduardo Gharzouzi, Michael Dean. Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1938.

Hereditary Cancer Syndrome in a Family with Double Mutation in BRIP1 and MUTYH Genes

Hereditary cancer syndromes predispose to several types of cancer due to inherited pathogenic variants in susceptibility genes. We describe the case of a 57-year-old woman, diagnosed with breast cancer, and her family. The proband belongs to a family with a suspected tumor syndrome, due to other cancer cases in her family from the paternal and maternal sides. After oncogenetic counseling, she was subjected to mutational analysis with an NGS panel analyzing 27 genes. The genetic analysis showed two monoallelic mutations in low penetrance genes, c.1187G>A (p.G396D) in MUTYH and c.55dup (p.Tyr19Leufs*2) in BRIP1. One of the mutations was inherited from the maternal side and the other from the paternal side, suggesting two different cancer syndrome types in the family. MUTYH mutation was related to the onset of cancers on the paternal side, as confirmed by the occurrence of the same mutation in the proband's cousin. BRIP1 mutation was found in the proband's mother, indicating that it was related to the cancer cases observed on the maternal side, including breast cancer and sarcoma. Advances in NGS technologies have allowed the identification of mutations in families with hereditary cancers in genes other than those related to a specific suspected syndrome. A complete oncogenetic counseling, together with molecular tests that enable a simultaneous analysis of multiple genes, is essential for the identification of a correct tumor syndrome and for clinical decision-making in a patient and his/her family. The detection of mutations in multiple susceptibility genes allows the initiation of early risk-reducing measures for identified mutation carriers among family members and to include them in a proper surveillance program for specific syndromes. Moreover, it may enable an adapted treatment for the affected patient, permitting personalized therapeutic options.

Abstract 5943: Association between the consumption of meat and carbonated drinks and early onset gastric cancer in Chilean patients

Abstract Gastric cancer (GC) is the 5th most frequent neoplasm and the 3rd cancer with the highest mortality according to GLOBOCAN. GC is often diagnosed in middle aged and elderly people, with a peak in incidence between 60 and 70 years old. In contrast, early-onset GC is the GC had a strong hereditary component. Associations of sporadic late onset-GC and dietary factors have been published but the role of nutritional factors in early onset GC is unknown. The aim of this study is to investigate the association between the intake of red meat, pork, processed meats and carbonated drinks in a group of early-onset GC. Our study was carried out in 19 Chilean early-onset GC patients, aged between 32 and 60 years, and 32 healthy age matched individuals from the same population. Through a survey of nutritional habits carried out retrospectively considering the stage prior to the diagnosis of GC, we determined the amount, type and frequency of ingestion of red meat, pork, processed meat and carbonated beverages. To measure the association an odds ratio and non-parametric association statistic tests were used. For the association of meat intake, we used the WHO recommendation (less than 70 g of meat per day) to classify the meat consumption levels in both groups. An odds ratio of 25.5 (4.8-135.4, p=8.3x105) was determined between the consumption of more than 70 g of meat per day in the early onset GC group vs the control group. Even though there are no international recommendations for carbonated drinks consumption levels, we found a higher carbonated drink consumption among cases (cases: Ave.= 180,7, SD= ±108,5 vs controls: Ave.=43,3, SD=±38,3. P=0033). In conclusion, our results shows significant associations between the consumption of red meat, pork, processed meats, and carbonated drinks in the risk of early-onset GC patients compared with the control group. Our findings, suggest that nutritional factors could play a role in the early GC presentation, acting in conjunction with low penetrance gene mutations. We will incorporate more early onset patients to the study group and do a sex matching for the control group to evaluate this possible confounding factor. We will also incorporate a late onset GC group. We think that nutritional factors could be an important factor to modulate genetic risk, even in early-onset patients. Beca Chile Postdoctorado 74190063 to GM. Citation Format: Carol Parra, Graciela Molina, Carla Coo, Jessica López, María San Martín, Javiera Siche, Luis Carvajal-Carmona. Association between the consumption of meat and carbonated drinks and early onset gastric cancer in Chilean patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5943.

Points to Consider Regarding Risk-Reducing Mastectomy in High-, Moderate-, and Low-Penetrance Gene Carriers.

Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with BRCA1/2 germline mutations. Multigene panels identify women with alterations in breast cancer susceptibility genes other than BRCA1/2. International guidelines classify these genes as high-, moderate-, and low-penetrance based on their associated relative risk for breast cancer. Classification of specific genes is not always concordant among guidelines, and the indications for risk-reducing mastectomy are not defined. In this opinion paper, we review some considerations to clarify these controversial points.

Association of polymorphisms in four low-penetrance genes (ACYP2, CCNE1, ERCC5 and lincRNA CASC22) with breast cancer risk in a Vietnamese population

In breast cancer (BC), four low-penetrance genes (ACYP2, CCNE1, ERCC5 and lincRNA CASC22) are involved in cell cycle arrest, DNA damage repair and long non-coding RNA-mediated regulation is commonly known as causative genes of tumorigenesis. A functional polymorphism in these genes may cause cancer by altering the genes' structure and function. Single Nucleotide Polymorphisms (SNPs) have been discovered to be capable of predicting cancer risk, hence can be used as carcinogenesis markers. To date, the correlation of four SNPs (rs12621038, rs3218038, rs751402 and rs12325489) with BC risk in different populations has been revealed by numerous researches. This study examines the association between these SNPs and the risk of developing BC in Vietnamese women. These four SNPs were genotyped by HRM assay. The differences in allelic and genotypic frequencies between cases and controls were analyzed to determine their relationship with BC risk. While rs12621038, rs3218038 and rs751402 showed no relation to BC, there was an association between rs12325489 and BC risk. In both codominant and overdominant models, the lincRNA CASC22 rs12325489 was consistently associated with BC risk (TT vs. CC: OR = 0.63, 95% CI = 0.44 to 0.90, P = 0.01 and TC vs. TT + CC: OR = 0.61, 95% CI = 0.43 to 0.84, P = 0.003; respectively). These results indicated that rs12325489 could be a potential biomarker for predicting BC risk in Vietnamese women.

Male Breast Cancer: From Molecular Genetics to Clinical Management.

Simple SummaryMale breast cancer (MBC) is a rare disease. Genetic factors predispose to male breast cancer. Germline and/or genetic and/or epigenetic alterations at the somatic level identify a subset of male breast cancer that could differ from female breast cancer (FBC). Cancer genetic counseling should be included in the work-up of male breast cancer to identify the possible genetic origin of the tumor and to offer patients and their at-risk family members adequate management.MBC is a rare disease accounting for almost 1% of all cancers in men and less than 1% of breast cancer. Emerging data on the genetic drivers of predisposition for MBC are available and different risk factors have been associated with its pathogenesis. Genetic alterations, such as pathogenetic variants in BRCA1/2 and other moderate-/low-penetrance genes, along with non-genetic risk factors, have been recognized as pathogenic factors for MBC. Preventive and therapeutic implications could be related to the detection of alterations in predisposing genes, especially BRCA1/2, and to the identification of oncogenic drivers different from FBC. However, approved treatments for MBC remain the same as FBC. Cancer genetic counseling has to be considered in the diagnostic work-up of MBC with or without positive oncological family history. Here, we review the literature, reporting recent data about this malignancy with a specific focus on epidemiology, and genetic and non-genetic risk factors. We introduce the perspective of cancer genetic counseling for MBC patients and their healthy at-risk family members, with a focus on different hereditary cancer syndromes.

Role of Moderate Risk Suseptibilty Genes in Development of Breast Cancer

Breast cancer is the most common cause of mortality in females globally and affects the lives of millions of women. It is a leading cause of mortality worldwide, but the dynamics have been changed because of advanced screening and treatment protocols [1]. In the United States, breast cancer has been ranked second most common cause of cancer-related death in women, with the most common being lung cancer [2]. To improve cancer screening, a personalized approach has been discussed, but its implication over large populations can be difficult and require expertise. Early detection leads to a good prognosis whereas the late diagnosis of breast cancer is a challenge for both patient and doctor [3]. Breast cancer became the most prevalently diagnosed cancer worldwide as of 2021 accounting for 12% of new annual cases worldwide, according to the World Health Organization. In2020, there were 2.3 million women diagnosed with breast cancer and 685 000 deaths globally. Multigene panel testing has identified various genes predisposed to breast cancer development. These genes have different penetrance abilities. BRCA1 and BRCA2 genes are the best known high penetrance gene of hereditary breast cancer. Their discovery has revolutionized the effect in cancer assessment. Tumors from BRCA1 and BRCA2 show distinctive clinicopathological characteristics as compared with other genes causing tumors. Beyond BRCA1 and BRCA2, advances in molecular technique have led to the identification of other genes associated with breast cancer. Some other the high penetrance genes are TP53, PTEN, STK11, and CDH1. Besides high pentrance gene, moderate to low penetrance genes are also recognized as a cancer predisposing genes: PALB, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D. Along with risk of breast cancer development these genes also predispose to other malignancies, as well as some genetic disorders.

Abstract 11792: Low Penetrance Sarcomere Variants Indicate an Additive Genetic Risk Model in Hypertrophic Cardiomyopathy

Introduction: Genetic hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition primarily due to pathogenic variants in sarcomere genes, often with marked clinical variability. We hypothesized that this variability may, in part, be due to additive effects from low penetrance sarcomere variants that would otherwise be dismissed due to high population prevalence. Methods: Low-penetrance HCM-associated sarcomere gene variants were identified by meeting a threshold for enrichment in HCM (ascertained from the Sarcomeric Human Cardiomyopathy Registry, SHaRe) versus the general population (ascertained from the Genome Aggregation Database, gnomAD), defined by an odds ratio (OR) &gt;5, and a population prevalence greater than the most common autosomal dominant pathogenic HCM variant, MYBPC3 R502W (4x10 -5 ). Clinical variables and time-event analyses were performed from SHaRe . Results: A total of 507 unique sarcomere gene variants were present in 6384 individuals with genetic testing. Ten putative low-penetrance variants were identified in the genes MYBPC3 (N=2), TNNT2 (N=1), TNNI3 (N=2), and MYH7 (N=5) with a combined OR of 12.7 (range 5.8 - 28.4). These variants had a population prevalence of 4.02x10 -5 to 3.5x10 -4 . Family members of low-penetrance variant carriers were less likely to have HCM (35/171, 20%) than those of MYBPC3 R502W carriers (44/113, 39%, p&lt;0.005). Age of diagnosis was older in patients with isolated low-penetrance variants than those with pathogenic variants (42 ± 19 vs 37 ± 18, p=0.005). Composite adverse events were less likely in patients with isolated low-penetrance variants than typical pathogenic sarcomere variants, but the risk was additive with both present (see Figure). Conclusions: A subset of low-penetrance sarcomere gene variants are tolerated in the general population at higher than expected proportions for HCM and may exert an additive pathogenic effect. These findings support an oligogenic risk model of HCM.

Melanoma in children and adolescents: analysis of susceptibility genes in 123 Italian patients.

A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients. We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents. One-hundred-twenty-three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated. Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi. Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

The context-specific role of germline pathogenicity in tumorigenesis.

Human cancers arise from environmental, heritable, and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced cancer patients, we identified pathogenic germline variants in cancer predisposition genes and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.

A pan-genome method to determine core regions of the Bacillus subtilis and Escherichia coli genomes.

Background: Synthetic engineering of bacteria to produce industrial products is a burgeoning field of research and application. In order to optimize genome design, designers need to understand which genes are essential, which are optimal for growth, and locations in the genome that will be tolerated by the organism when inserting engineered cassettes. Methods: We present a pan-genome based method for the identification of core regions in a genome that are strongly conserved at the species level. Results: We show that the core regions determined by our method contain all or almost all essential genes. This demonstrates the accuracy of our method as essential genes should be core genes. We show that we outperform previous methods by this measure. We also explain why there are exceptions to this rule for our method. Conclusions: We assert that synthetic engineers should avoid deleting or inserting into these core regions unless they understand and are manipulating the function of the genes in that region. Similarly, if the designer wishes to streamline the genome, non-core regions and in particular low penetrance genes would be good targets for deletion. Care should be taken to remove entire cassettes with similar penetrance of the genes within cassettes as they may harbor toxin/antitoxin genes which need to be removed in tandem. The bioinformatic approach introduced here saves considerable time and effort relative to knockout studies on single isolates of a given species and captures a broad understanding of the conservation of genes that are core to a species.