PALB2 Research Articles

A novel germline mutation of the <i>PALB</i> gene in a young Yakut breast cancer woman

Background. Breast cancer (BC) is the most common female malignancy worldwide. partner and localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. the goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHIA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results. Here we describe a case of a never-before-reported mutation in the PALB gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47dela:p.K16fs). in accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

Male breast cancer - a review on risk factors, tumor characteristics, diagnostics and treatment

Introduction and purpose:
 Male breast cancer (MBC) is estimated to less than 1% of all breast cancer cases worldwide. A lifetime risk of developing MBC amounts to 1:1000. The data on breast cancer in men is limited. This review aims to analyze information on risk factors, diagnostics and treatment in men suffering from breast cancer. 
 Material and method:
 This review was based on available data collected in PubMed and published in the years 2001-2022. The research was done by looking through keywords as follows: “breast cancer”, “male breast cancer”, “risk factors” and “treatment”.
 Results:
 Male breast cancer usually manifests as a painless, retroareolar mass in the breast. Risk factors include advanced age, hormonal imbalance, exposure to radiation and a positive family history. A significant risk increase in MBC development occurs in BRCA2, CHEK2, PALB2 and ATM genes mutations. G2 ductal carcinoma with no special type is most often diagnosed. Dominating subtype is luminal A cancer, while HER2 protein overexpression is extremely rare. Radical mastectomy or breast conserving therapy remain surgical therapeutic options. The most preferred endocrine therapy is tamoxifen. The choice of chemotherapy in men is based on the same criteria as in women. 
 Conclusions:
 Delayed diagnosis and tumor characteristics are associated with a much worse prognosis for men compared to women. Therefore, further clinical research is crucial in order to improve the diagnostic possibilities and treatment targeted at men with this type of cancer.

Strong founder effect for BRCA1 c.3629_3630delAG pathogenic variant in Chechen patients with breast or ovarian cancer.

Coding sequences of BRCA1, BRCA2, ATM, TP53, and PALB2 genes were analyzed in 68 consecutive Chechen patients with high-grade serous ovarian cancer (HGSOC). Pathogenic BRCA1/2 variants were identified in 15 (22%) out of 68 HGSOC cases. Nine out of ten patients with BRCA1 pathogenic alleles carried the same deletion (c.3629_3630delAG), and three out of five BRCA2 heterozygotes had Q3299X allele. The analysis of 49 consecutive patients with triple-negative breast cancer (TNBC) revealed 3 (6%) additional BRCA1 heterozygotes. All women with BRCA1 c.3629_3630delAG allele also carried linked c.1067G>A (Q356R) single nucleotide polymorphism, indicating that this is a genuine founder variant but not a mutational hotspot. An ATM truncating allele was detected in one HGSOC patient. There were no women with TP53 or PALB2 germline alterations. Genetic analysis of non-selected HGSOC patients is an efficient tool for the identification of ethnicity-specific BRCA1/2 pathogenic variants.

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.

The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

Multi-gene panel testing increases germline predisposing mutations' detection in a cohort of breast/ovarian cancer patients from Southern Italy.

Breast cancer is the most common neoplasia in females worldwide, about 10% being hereditary/familial and due to DNA variants in cancer-predisposing genes, such as the highly penetrant BRCA1/BRCA2 genes. However, their variants explain up to 25% of the suspected hereditary/familial cases. The availability of NGS methodologies has prompted research in this field. With the aim to improve the diagnostic sensitivity of molecular testing, a custom designed panel of 44 genes, including also non-coding regions and 5’ and 3’ UTR regions, was set up. Here, are reported the results obtained in a cohort of 64 patients, including also few males, from Southern Italy. All patients had a positive personal and/or familial history for breast and other cancers, but tested negative to routine BRCA analysis. After obtaining their written informed consent, a genomic DNA sample/patient was used to obtain an enriched DNA library, then analyzed by NGS. Sequencing data analysis allowed the identification of pathogenic variants in 12 of tested patients (19%). Interestingly, MUTYH was the most frequently altered gene, followed by RNASEL, ATM, MSH6, MRE11A, and PALB2 genes. The reported resultsreinforce the need for enlarged molecular testing beyond BRCA genes, at least in patients with a personal and familial history, strongly suggestive for a hereditary/familial form. This gives also a hint to pursue more specific precision oncology therapy.

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants.

PurposeThere is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará.MethodsPatients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes.ResultsA total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort.ConclusionIn this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management.

The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer.

(1) Background: Germline variants in BRCA1/BRCA2 genes explain about 20% of hereditary breast/ovarian cancer (HBOC) cases. In the present paper, we aim to identify genetic determinants in BRCA-negative families from the South of Tunisia. (2) Methods: Exome Sequencing (ES) was performed on the lymphocyte DNA of patients negative for BRCA mutations from each Tunisian family with a high risk of HBOC. (3) Results: We focus on the canonical genes associated with HBOC and identified missense variants in DNA damage response genes, such as ATM, RAD52, and RAD54; however, no variants in PALB2, Chek2, and TP53 genes were found. To identify novel candidate genes, we selected variants harboring a loss of function and identified 17 stop-gain and 11 frameshift variants in genes not commonly known to be predisposed to HBOC. Then, we focus on rare and high-impact genes shared by at least 3 unrelated patients from each family and selected 16 gene variants. Through combined data analysis from MCODE with gene ontology and KEGG pathways, a short list of eight candidate genes (ATM, EP300, LAMA1, LAMC2, TNNI3, MYLK, COL11A2, and LAMB3) was created. The impact of the 24 selected genes on survival was analyzed using the TCGA data resulting in a selection of five candidate genes (EP300, KMT2C, RHPN2, HSPG2, and CCR3) that showed a significant association with survival. (4) Conclusions: We identify novel candidate genes predisposed to HBOC that need to be validated in larger cohorts and investigated by analyzing the co-segregation of selected variants in affected families and the locus-specific loss of heterozygosity to highlight their relevance for HBOC risk.

Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2

Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.

Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes.

Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.

PALB2 gene in breast cancer

Breast cancer represents the most commonly encountered form of malignant disease in women worldwide, which has been widely demonstrated to have a strong genetic predisposition. Therefore, it seems that most often it is inherited in an autosomal dominant manner, the most commonly encountered germline gene variant being represented by BRCA 1 and BRCA 2, followed by TP53, CDH1, PTEN and STK1. Recently PALB2 gene has been demonstrated to confer a moderate risk for breast cancer development. In this article the importance and the prevalence of the PALB2 gene is presented as well as the breast cancer risk is analyzed (based on various studies). To better manage and understand the risks we have detailed the newest monitoring and treatment options regarding a mutation in the PALB2 gene that leads to breast cancer.

Abstract 5682: Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue

Abstract During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. We show that histologically normal breast tissue from younger women who are susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibit hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory, and cancer-related pathways. Genetically high risk luminal epithelial cells also show evidence of accelerated age, by as much as four decades compared to their chronological age, using a breast specific biological clock comprised of measurements of methylation and expression of the luminal-specific ELF5 transcription factor. We have identified breast aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk, or the associated breast cancer subtype. Citation Format: Masaru Miyano, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, Mark A. LaBarge. Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue [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 5682.

Abstract 52: Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib

Abstract Tumor cells of metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) are highly sensitive to the blockade of DNA single-strand break repair via the inhibition of the poly(adenosine diphosphate-ribose) polymerase (PARP) family of nuclear proteins. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases, and the Resolution HRD assay is being developed as a companion diagnostic for niraparib. Detection of HRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and is of special benefit to mCRPC patients, many without accessible lesions. The Resolution HRD assay identifies patients with substitutions, insertions, deletions, and homozygous deletions of the ATM, BRCA1, BRCA2, BRIP1, CDK12 (except homozygous deletions), CHEK2, FANCA, HDAC2, and PALB2 genes by targeted NGS sequencing of cfDNA isolated from plasma. Analytical performance of the Resolution HRD assay was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations along with CRISPR-engineered human cell lines with ATM and BRCA2 gene deletions. The LOD95 was established for substitutions, insertions, deletions, and homozygous deletions for genes represented in the HRD panel with variant types including complex indels, long indels, and challenging genomic settings including homopolymeric and GC-rich regions. mCRPC specimens were used to confirm an acceptable level of precision near 1X LOD and 2-3X LOD concentrations for all 4 variant types. No false-positives were detected in any samples from healthy donors. Resolution HRD has been validated to give consistent results across the 15-30 ng input range. Studies to confirm accuracy of the Resolution HRD test results using a validated orthogonal method will be presented. The Resolution HRD assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. It is intended as a companion diagnostic to niraparib in combination with abiraterone acetate plus prednisone (AAP) for the treatment of mCRPC patients. Citation Format: Julia Pollak, Kristy Potts, PuiYee Chan, Chen-Hsun Tsai, Angela Liao, Carly Garrison, Taylor Brown, Paul Stull, Zhen Li, Christine Baker, Kavita Garg, Ira Pekker, Michael Farabaugh, Michael Gormley, Lesley Farrington, Katherine Bell, Usha Singh. Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib [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 52.

Abstract 798: Comprehensive genomic profiling of tissue and liquid biopsies reveals the landscape of reversion mutations

Abstract Loss of function mutations in homologous recombination (HR) repair genes predispose individuals to cancer due to the genomic instability brought about by the inability to properly repair DNA. These alterations may also identify patients eligible for treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and platinum drugs that exploit synthetic lethality; however, resistance eventually occurs. This resistance is largely the result of reversion mutations, which restore the DNA repair function of mutated HR genes. We employed a computational approach to identify patients with breast, ovarian, pancreas, or prostate cancer who underwent comprehensive genomic profiling (CGP; Foundation Medicine, Inc.) and had reversion mutations in the BRCA1, BRCA2, PALB2, RAD51C, or RAD51D genes. Reversion mutations were identified in six different categories: 1) missense mutations that occur at the same amino acid position as a deleterious alteration, 2) non-frameshift deletion mutations that encompass a deleterious alteration, 3) frameshift mutations that restore the open reading frame of another frameshift mutation, 4) splice-site mutations that occur at the same exon as a deleterious alteration, 5) copy number losses that remove a deleterious alteration, and 6) intragenic deletions that lead to loss of deleterious mutation. Using our computational approach, we identified 483 patients who 1,112 reversion mutation pairs in both solid tissue- and liquid biopsy-derived samples. The most frequently observed category was a non-frameshift deletion of a deleterious mutation. Overall, a greater number of reversion mutations were found in liquid biopsy samples. BRCA2 was the most frequently reverted gene followed by BRCA1, PALB2, RAD51D, and RAD51C. BRCA1-mutated samples had up to six reversion mutations, and for BRCA2, we observed as many as 228 putative reversion pairs in one sample. PALB2, RAD51C, and RAD51D had no more than two reversion mutations. We further examined co-occurring alterations and found correlations with genes in multiple signaling pathways including the MYC signaling pathway, which contained more mutations in reversion-positive samples. Lastly, we explored real-world longitudinal data from reversion-positive samples and found that the presence of a reversion mutation was significantly associated with lower overall survival for breast, ovarian, and prostate cancer patients. In summary, we characterized the landscape of reversion mutations in patients who underwent tissue or liquid biopsy-based CGP during clinical cancer treatment. Our data provide a better perspective for the identification and treatment of cancers involving a reversion mechanism. Citation Format: Shannon T. Bailey, Meijuan Li, James Thornton, Lei Yang, Chenming Cui, Mark Hartman, Garrett Frampton, Brennan Decker, Christine Vietz. Comprehensive genomic profiling of tissue and liquid biopsies reveals the landscape of reversion mutations [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 798.

Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations.

Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women. The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03-46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17-15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15-138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72-6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P < 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks. We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries. These findings have direct relevance for breast cancer genetic counseling for women in West Africa.

2P Spectrum of BRCA1, BRCA1, ATM and PALB2 alleles in ovarian cancer patients from North Caucasus

BackgroundNorth Caucasus hosts several large ethnic groups, which preserved their national identity through the course of history. These populations are likely to have a unique pattern of disease-predisposing alleles reflecting the genetic background of their ancestors.MethodsThis study involved 180 ovarian cancer (OC) patients from Chechnya (n = 68), Kabardino-Balkaria (n = 49), North Ossetia (n = 32), Ingushetia (n = 16) and Dagestan (n = 15). The entire coding sequences of BRCA1, BRCA2, ATM and PALB2 genes were analyzed by next-generation sequencing.ResultsOC patients belonging to various ethnic groups had high frequency of BRCA1/2 mutations ranging from 18% to 33%. There were founder pathogenic alleles detected in Chechens (BRCA1 c.3629_3630delAG; 9 out of 15 BRCA1/2 mutations) and North Ossetians (BRCA2 c.6341delC; 6 out 8 BRCA1/2 mutations). Interestingly, Chechen BRCA1 c.3629_3630delAG allele was not present among patients of Ingush ethnicity, despite these nations are believed to have common roots. BRCA2 Q3299X mutation was repeatedly observed across several ethnic groups. Patients from Kabardino-Balkaria had unusually high frequency of germ-line ATM truncating alleles (3/49, 6%); all 3 ATM mutations were represented by distinct ATM pathogenic variants. There were no instances of PALB2 germ-line mutations.ConclusionsGenetic analysis of ovarian cancer patients is efficient in revealing ethnicity-specific BRCA1/2 mutations. Contribution of BRCA1/2 pathogenic alleles in OC morbidity is high across various ethnic groups. Founder BRCA1/2 alleles are characteristic for some but not all North Caucasus nations.Legal entity responsible for the studyThe authors.FundingThis study has been supported by the Russian Science Foundation, grant 21-75-30015.DisclosureAll authors have declared no conflicts of interest. BackgroundNorth Caucasus hosts several large ethnic groups, which preserved their national identity through the course of history. These populations are likely to have a unique pattern of disease-predisposing alleles reflecting the genetic background of their ancestors. North Caucasus hosts several large ethnic groups, which preserved their national identity through the course of history. These populations are likely to have a unique pattern of disease-predisposing alleles reflecting the genetic background of their ancestors. MethodsThis study involved 180 ovarian cancer (OC) patients from Chechnya (n = 68), Kabardino-Balkaria (n = 49), North Ossetia (n = 32), Ingushetia (n = 16) and Dagestan (n = 15). The entire coding sequences of BRCA1, BRCA2, ATM and PALB2 genes were analyzed by next-generation sequencing. This study involved 180 ovarian cancer (OC) patients from Chechnya (n = 68), Kabardino-Balkaria (n = 49), North Ossetia (n = 32), Ingushetia (n = 16) and Dagestan (n = 15). The entire coding sequences of BRCA1, BRCA2, ATM and PALB2 genes were analyzed by next-generation sequencing. ResultsOC patients belonging to various ethnic groups had high frequency of BRCA1/2 mutations ranging from 18% to 33%. There were founder pathogenic alleles detected in Chechens (BRCA1 c.3629_3630delAG; 9 out of 15 BRCA1/2 mutations) and North Ossetians (BRCA2 c.6341delC; 6 out 8 BRCA1/2 mutations). Interestingly, Chechen BRCA1 c.3629_3630delAG allele was not present among patients of Ingush ethnicity, despite these nations are believed to have common roots. BRCA2 Q3299X mutation was repeatedly observed across several ethnic groups. Patients from Kabardino-Balkaria had unusually high frequency of germ-line ATM truncating alleles (3/49, 6%); all 3 ATM mutations were represented by distinct ATM pathogenic variants. There were no instances of PALB2 germ-line mutations. OC patients belonging to various ethnic groups had high frequency of BRCA1/2 mutations ranging from 18% to 33%. There were founder pathogenic alleles detected in Chechens (BRCA1 c.3629_3630delAG; 9 out of 15 BRCA1/2 mutations) and North Ossetians (BRCA2 c.6341delC; 6 out 8 BRCA1/2 mutations). Interestingly, Chechen BRCA1 c.3629_3630delAG allele was not present among patients of Ingush ethnicity, despite these nations are believed to have common roots. BRCA2 Q3299X mutation was repeatedly observed across several ethnic groups. Patients from Kabardino-Balkaria had unusually high frequency of germ-line ATM truncating alleles (3/49, 6%); all 3 ATM mutations were represented by distinct ATM pathogenic variants. There were no instances of PALB2 germ-line mutations. ConclusionsGenetic analysis of ovarian cancer patients is efficient in revealing ethnicity-specific BRCA1/2 mutations. Contribution of BRCA1/2 pathogenic alleles in OC morbidity is high across various ethnic groups. Founder BRCA1/2 alleles are characteristic for some but not all North Caucasus nations. Genetic analysis of ovarian cancer patients is efficient in revealing ethnicity-specific BRCA1/2 mutations. Contribution of BRCA1/2 pathogenic alleles in OC morbidity is high across various ethnic groups. Founder BRCA1/2 alleles are characteristic for some but not all North Caucasus nations.

Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]

Heart toxicity effects (HTE) of anthracyclines-containing regimens (ACRs) in patients with breast cancer (BC) carrying mutational signature of homologous recombination deficiency (HRD).

10519 Background: BRCA1/2 genes ( BRCA) play a prominent role in the Homologous Recombination Repair (HRR) pathway. Following the technological progress and deeper knowledge on BRCA-related cancers, the demand for genetic testing is rapidly increasing. Beyond BRCA1/2, other genes are involved in the HRR, including ATM, PALB2, RAD51, and BARD1. Due to the important role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no- BRCA genes is still unknown. Methods: This is a multicenter, retrospective, study to investigate the risk of heart-insults from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) (classes IV and V) in BRCA and no- BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting ACR therapy, and at subsequent time points, according to clinical indications. Results: Three hundred and sixty (360) BC patients, aging 22 to 80, were included in this study; 131 patients were carriers of germline PVs in HRR pathway genes: 52 in BRCA1 gene (39.7%), 48 in BRCA2 gene (36.6%), and 31 harbored PVs in no- BRCA HRR pathway genes (23.7%), including PVs in PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 229 patients without PVs, 47 showed variant of uncertain significance (VUS, class III), and 173 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction of LVEF > 5% at the second time-point (3 month), compared to the LVEF pre-treatment values (p = 0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, body mass index > 25, and type-II diabetes mellitus. The latter risk factor was probably related to increased risk developing insulin-resistance reported for BRCA-mutated patients. Conclusions: Our data suggest that PVs in BRCA or other genes involved in HRR pathway, can lead to impaired homologous recombination, thus increasing sensitivity of cardiac cells to DNA damaging chemotherapy in BC patients. In this subgroup of patients, other measurements such as the global longitudinal strain (GLS), and a more in-depth assessment of risk factors, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.

15 years of experience of an oncogenetics service in the northeast of Brazil.

e22522 Background: The Oncogenetics service at the Federal University of Bahia was implemented in 2007 and since then has been offering pre- and post-test genetic counseling for cancer susceptibility genes, mainly tumors associated with King's syndrome in the population of the state of Bahia. This is a mixed population of about 80% of African ancestry. Methods: Between the years 2007 to 2021, 462 probands and their families have already been evaluated by NGS analysis, Sanger sequencing. Large rearrangements were detected by multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 and BRCA2 genes. Results: The mean age at diagnosis was 41 years. Pathogenic/probably pathogenic mutations were founded in 118 patients: 67 had breast cancer, 09 with ovarian cancer, 26 with more than one tumor, 15 without cancer, and 01 with another tumor type. Most of the pathogenic variants were located in the BRCA1 gene (27 variants), the two most frequent variants being: c.211G > A (13 probands) and c.3331_3334delCAAG (18 probands), both of Iberian origin. Of patients with mutation, 9.8% had large rearrangements in BRCA1 and 11.5% in BRCA2. Bilateral breast cancer appears predominantly in patients with BRCA1 (4) and BRCA2 (1) variants. In this study, only two mutations in BRCA described as of African origin were found in two patients. Other pathogenic mutations appear in ATM, BARD1, BRIP1, CDH1, CHEK2, FAM175A, FANCM, MSH6, NBN, NF2, PALB2, RAD51, SDHB, SLX4, and TP53 genes. Variants of uncertain significance were identified in 71 patients. Conclusions: The population of the state of Bahia has a peculiar mutational profile, containing mutations that are not very frequent in other regions of the country. Despite being a population with high African ancestry, most mutations are of European origin.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Simple SummaryThe clinical utility of positive findings in DNA damage-repair (DDR) genes BRCA1 and BRCA2 for the treatment of patients with breast or ovarian cancer is well established. However, multigene panel genetic testing for patients with breast and ovarian cancer now commonly includes DDR genes in addition to BRCA1 and BRCA2, a number of which are considered moderate or low-risk genes. This study aimed to describe the clinical utility of positive results from genetic testing when the findings were in one of these other DDR genes. In a group of 101 women with positive findings in a cancer gene other than BRCA1 or BRCA2 (often in a DDR gene), nearly three-fifths (58%) had a clinical recommendation made based on their positive genetic test result and two-thirds (65%) had the clinician make recommendations for family members that may be at risk. This real-world data provides evidence that positive findings from genetic testing for moderate and low-risk genes, including DDR genes, can have clinical utility and can impact a patient’s clinical management.Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients’ family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil

PurposeThere is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil.MethodsWe performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program.ResultsThe study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases.ConclusionThe high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.