PALB2 Research Articles

Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer

BackgroundHigh-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 557 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations (SCNA).ResultsApproximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2. LOF germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1. In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of LOF variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival.ConclusionsFrom 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

Germline mutations in the PALB2 and CHEK2 genes and hereditary cancer

Introduction. At least 3% of all cancer cases are associated with hereditary changes in genes predisposing to malignant neoplasms. In addition to the widely known BRCA1,2 genes, other genes involved equally with BRCA1,2 in the DNA repair system and maintenance of genome integrity, such as PALB2, CHEK2, are being introduced into routine diagnosis. In this review we present current information from recent studies on the structure and function of PALB2 and CHEK2 genes, and the diagnosis of mutations in these genes, as well as their clinical significance.The purpose of this work was to update and systematize the data on PALB2 and CHEK2 genes in order to better understand their significance in carcinogenesis, associated risks of malignant neoplasms, prevention and treatment tactics for mutation carriers.Materials and methods. PubMed, Google Scholar, Cyberleninka databases were searched. The criteria for inclusion of articles were the novelty and relevance of the data, compliance to the topic of the review. Based on this, 79 literary sources were selected.Results and discussion. Mutations in the PALB2 gene are common in 0.5 to 2.1 % of cancer cases and are associated with an increased risk of breast cancer (52.8 % by age 80), as well as ovarian cancer (5 %), pancreatic cancer (2.8 %). The frequency of changes in the CHEK2 gene reaches 5 % and is associated with a risk of breast cancer (up to 40 % by age 80) and colorectal cancer. Numerous studies have shown that mutations in these genes are associated with prostate, lung, kidney, and melanoma cancers.Conclusion. A better understanding of the spectrum of genetic predisposition and identification of genespecific cancer risks could lead to improved screening, prevention, and therapeutic strategies for patients with hereditary cancer and their families.

Study protocol to assess the quality of life after preventive bilateral salpingo-oophorectomy in BRCA1/2 and PALB2 mutation carriers

Introduction: Pathogenic variants in BRCA1, BRCA2 and PALB2 genes are associated with a high lifetime breast cancer (BC) and a high or moderate ovarian cancer (OC) risk, respectively. Preventive bilateral salpingo-oophorectomy (PBSO) is a mortality reducing strategy recommended to healthy carriers at the age of 35–40 or after completion of childbearing. The main reason for delaying surgery is women´s fear of the impact of premature menopause on quality of life and long-term health risks.

Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study

BackgroundInitial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration. ObjectiveTo present the final data from TRITON2. Design, setting, and participantsTRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint. Results and limitationsAs of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35–57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40–100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5–57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46–61%), 55% (23–83%), 3.4% (0.4–12), 6.7% (0.2–32%), 14% (0.4–58%), and 23% (5.0–54%), respectively. ConclusionsThe final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene. Patient summaryAlmost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

Prevalence of pathogenic variants in non-BRCA genes and their impact on clinical practice in Argentina.

e22534 Background: The use of NGS has made it easier and more cost-effective to analyze genes associated with hereditary cancer predisposition syndromes. Germline alterations in breast cancer (BC) have an estimated prevalence of 10.7% of Pathogenic Variant or Likely Pathogenic (P/LP), with up to 8.0% in BRCA1/2 and 2.7% in CHEK2, ATM and PALB2 genes; they increase the risk of cancer 2 to 5 times. To date, two studies of P/LP in genes non-BRCA1/2 have been conducted in Argentina with frequencies of 4.5 and 4.7% in patients with personal and/or family history of BC. Methods: We report the frequency of P/LP in non-BRCA1/2 genes in patients with hereditary cancer criteria referred to the Oncogenetics Program at Hospital Privado Universitario de Córdoba between 01/2016 and 12/2022. A retrospective analysis was conducted on patients with BC, ovarian cancer (OC), pancreatic cancer (PaC), or prostate cancer (PC) who had clinical criteria for hereditary cancer. NGS and/or Sanger methods were used to sequence the samples, and the frequency of P/LP, novel P, and their association with other variants were collected and associated with the clinical features of the index case. Results: Of 283 cases studied, 85 (30.0%) were P/LP, with 53 (18.7%) detected in BRCA1/2 and 32 (11.3%) in other genes. Among the 32 mutations found in non-BRCA1/2 genes, the frequency of P/LP was 4.59% for PALB2 and 2.47% for CHEK2, 1.06% for TP53, 0.7% for MUTHY and 0.35% each for ATM, BRIP1, FANCC, MLH1, MSH2, FANCM and PTEN. The cases studied correspond to BC (75%), PaC (9.3%) and asymptomatic patients (15.7%), two of which belonged to families with an identified mutation in PALB2, other two in CHEK2, and one with no available index case with a mutation in ATM. The age at diagnosis in the cases with personal history was 44.5 years (20-66) with a very early age in the cases with TP53 mutations and two cases with PALB2 variants. Of the total mutations in non-BRCA1/2 genes, two were found to be associated with other pathogenic mutations and 12 were associated with VUS. Within our study, four remarkable findings were identified in PALB2 gene: 1) five unrelated families share the pathogenic c.1653T > A; 2) two unrelated families share the pathogenic c.1959T > A; 3) the novel c.2872_2875del LP variant was detected and 4) the frequency of the variant c.1653T > A suggests the possibility of a founder effect. Our study shows a higher frequency of P/LP in non-BRCA genes than those reported in Argentina and Latin America, which may be due to the selection of a population with family and/or personal history of cancer. Conclusions: It is important to perform multi-gene testing including moderate-penetrance genes to determine the hereditary susceptibility to cancer in our population and to identify vulnerable groups that require more specialized surveillance than the general population. This will help individuals with a higher risk of developing cancer to take effective preventive actions.

Radiosensitivity and early onset cancer

The article is concerned with the radioprotection of a substantial radiosensitive population who present with cancer in early adulthood and will probably be treated with radiotherapy. A theory of radiation-induced health effects based on the induction of DNA double strand breaks is used to associate the radio-sensitivity of carriers of the BRCA1 and BRCA2 genes and the PALB2 gene with the defects in the homologous recombination repair of DNA damage found in the carriers. It is concluded that the defects in homologous recombination repair in these carriers will lead to an increased level of somatic mutations in all their cells and that this increased level of somatic mutations throughout their lifetime is, essentially, the reason that the carriers develop early onset cancer. This is a direct consequence of the more rapid accumulation of the cancer-inducing somatic mutations than the normal, slower accumulation in non-carriers. The radiotherapeutic treatment of these carriers needs to proceed with some care, taking account of their increased radio-sensitivity, and this suggests a need for international recognition and guidance of their radioprotection within the medical profession.

Homologous recombination pathway gene variants identified by tumor-only sequencing assays in lung carcinoma patients.

The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype. Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas. Cases were filtered for variants (disease-associated or of uncertain significance) in 14 HR pathway genes, including BRCA1, BRCA2, and ATM. The clinical, pathological and molecular data were reviewed. Sixty-one HR pathway gene variants in 56 patients with primary lung cancer were identified. Further filtering by variant allele fraction (VAF) of ≥30% identified 17 HR pathway gene variants in 17 patients. ATM gene variants were most the commonly identified (9/17), including two patients with c.7271T>G (p.V2424G), a variant in the germline that is associated with increased familial cancer risk. Four (4/17) patients had a family history of lung cancer, among which three patients had ATM gene variants suspected to be germline in origin. In three other patients with BRCA1/2 or PALB2 gene variants who had undergone germline testing, the variants were confirmed to be germline; lung cancer was the sentinel cancer in two of these patients with a BRCA1 or PALB2 variant. Genomic variants in the HR repair pathway identified in tumor-only sequencing and occurring at higher VAFs (i.e., ≥30%) may suggest a germline origin. Correlating with personal and family history, a subset of these variants is also suggested to be associated with familial cancer risks. Patient age, smoking history and driver mutation status are expected to be a poor screening tool in identifying these patients. Finally, the relative enrichment for ATM variants in our cohort suggests a possible association between ATM mutation and lung cancer risk.

Following in the footsteps of SABCS 2022: top 16 early breast cancer studies that could change our clinical practice: A review

A review of the studies presented at the SABCS 2022 conference on the treatment of breast cancer (BC) has been carried out; 16 of the most exciting and significant works reported at oral or poster sessions have been identified. Data from large randomized and population-based studies were presented, including TAM-01 (the role of adjuvant therapy with 5 mg tamoxifen for in situ cancer), six studies on the surgical treatment of early breast cancer, including a meta-analysis to assess the effect of surgery extent on overall survival, a comparison of the results of targeted lymph node dissection and biopsy of sentinel lymph nodes in patients after neoadjuvant systemic therapy, an analysis of the local relapse rate after breast-conserving surgery in patients with multicentric breast cancer, as well as the effect of carrier status of pathogenic variants of mutations in the ATM, BRCA1, BRCA2, CHEK2 and PALB2 genes on the occurrence of cancer of the contralateral breast. Among the systemic therapy studies, the 10-years results of APT trial, Peony trial were presented, as well as the results of the TMC analysis on the various roles of carboplatin addition in neoadjuvant chemotherapy regimens in patients younger and older than 50 years with triple-negative breast cancer, randomized clinical studies on the escalation of adjuvant endocrine therapy in high relapse risk groups (MonarchE and SWOG S1207), as well as new data on cognitive dysfunction after chemotherapy in patients in the RxPONDER trial. Also noteworthy are the reviews of treatment in special clinical situations: the first results of the POSITIVE trial (an assessment of the oncological and obstetric outcomes of interruption of adjuvant endocrine therapy for conception), an analysis of the mortality of males with breast cancer over the past 20 years, as well as an analysis of the methylmalonic acid effect on senile weakness in patients with early breast cancer.

PALB2 germline mutations in a large cohort of Middle Eastern breast-ovarian cancer patients

The PALB2 gene is a breast cancer (BC) and ovarian cancer (OC) predisposition gene involved in the homologous recombination repair pathway. However, the prevalence and clinicopathological association of PALB2 pathogenic/likely pathogenic (PV/LPV) variants in Middle East is still not fully explored. Total 918 BC/OC patients from Saudi Arabia were selected for PALB2 mutations screening using capture sequencing technology. Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-2_2835-1delinsTT). One recurrent LPV (c.3425delT: p.L1142fs) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34–49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors. Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi BC and/or OC. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients.

The association between age at breast cancer diagnosis and prevalence of pathogenic variants

PurposeYoung age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2.MethodsWe analyzed multi-gene panel testing results (09/2013–12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry.ResultsAn association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64–4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84–2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08–1.37) and CHEK2 (OR 1.34, 95% CI 1.21–1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98–1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13–2.56) and BRCA2 (OR 1.25, 95% CI 1.16–1.35).ConclusionsYoung age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.

Abstract 6086: PALB2 germline mutations in a large cohort Middle Eastern breast-ovarian cancer patients

Abstract Background: The PALB2 gene encoding protein is involved in the homologous recombination repair pathway and plays an important role in maintaining genomic integrity. PALB2 heterozygous pathological variants (PV) or likely pathogenic variants (LPV) are associated with increased risk of breast and ovarian cancer. However, the prevalence and clinicopathological association of PALB2 germline PV/LPV in Middle Eastern breast and ovarian cancers is not fully identified. Purpose: We retrospectively screened a cohort of 918 cancer patients (791 breast cancer and 127 ovarian cancer) from Saudi Arabia using targeted capture-based next generation sequencing (NGS) method for PALB2 germline variants regardless the family history of these patients or the presence of other hereditary cancer susceptibility genes mutations. Clinicopathological criteria were also fully analyzed. Results: Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-1 C>A). One recurrent LPV (c.3425delT) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34-49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors. Conclusion: Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi breast and/or ovarian cancer. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients. Citation Format: Rong Bu, Abdul K. Sira, Sandeep Parvathareddy, Kaleem Iqbal, Saud Azam, Zeeshan Qadri, Maha Al-Rasheed, Wael Haqawi, Mark Diaz, Ingrid G. Victoria, Khawla S. Al-Kuraya. PALB2 germline mutations in a large cohort Middle Eastern breast-ovarian cancer patients [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 6086.

Abstract PR006: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

Abstract Effects from aging in any single cell are unpredictable, whereas aging phenotypes at the organ and tissue levels tend to appear as stereotypical changes. The mammary epithelium, the origin of breast carcinomas, is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. We have shown that luminal epithelia exhibit substantial stereotypical changes with age, which merits attention as they are putative breast cancer cells of origin. Hallmark aging changes in mammary gland are loss of lineage specificity in luminal epithelia exemplified by acquiring expression of proteins normally reserved for myoepithelial cells, and progenitor cells that accumulate and attain a basal differentiation bias. We hypothesize that effects from aging that impinge upon maintenance of lineage specificity increases susceptibility to cancer initiation. Indeed, histologically normal breast tissue from young women, who were known to be highly susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibited hallmarks of accelerated aging. These included increased proportions of luminal epithelial cells with acquired myoepithelial proteins, acceleration of a breast specific biological clock by 10 to 40 years compared to chronological age, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. To gain insight into the underlying molecular changes we interrogated transcriptomes, proteomes, and methylomes of mammary epithelia at lineage resolution. Strikingly, age-dependent differential gene expression and DNA methylation occurred almost exclusively in luminal epithelia, whereas changes due to increased variance of gene and protein expression occurs in both luminal and myoepithelial lineages. Most gene changes that were previously associated with early breast cancer are detectable as age-driven changes in normal luminal epithelia. The genes with age-dependent differential and variant changes in expression distinguish normal tissue from breast cancers and are predictive of PAM50 breast cancer subtypes. Heterochronus, multilineage, co-cultures demonstrated that the age-dependent phenotype of luminal cells is at least partly dependent on the microenvironment created on the apical surfaces of neighboring myoepithelial cells. We show that increased variance is a substantial outcome of aging and is likely central to understanding increased susceptibility to breast cancer with age. We speculate that the luminal epithelium is a site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype of aging both endows cells with the ability to become a cancer cell of origin and embodies a biosensor that presages one’s cancer susceptibility. Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR006.

Genetic, Surgical and Oncological Approach to Breast Cancer, with BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 Variants.

The aim of this study was to determine the frequency of germline variants in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 in patients admitted to a medical genetics clinic with breast cancer and to assess these identified variants according to published genetic, surgical and oncological perspectives. Medical history, and cancer diagnosis information for 195 independent probands with operated breast cancer were collected from requisition forms and medical records. The exonic regions and exon-intron junctions in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 genes were sequenced. Analysis of fastq files was performed on the Qiagen Clinical Insight-Analyse Universal with panel-specific pipeline and vcf files were interpreted clinically using Qiagen Clinical Insight-Interpret. Gene variants (pathogenic, likely pathogenic and variants of unknown significance) were detected in 53 (27.2%). Detailed information about the patients (age of diagnosis, family history, gender), cancer stage, tumour characteristics (ER, PR, human epidermal growth factor receptor 2 status) and all information related to the detected variants (gene, location, nucleotide and amino acid change, exon number, impact, mutation classification, dbSNP number and HGMD variant class) were assessed. In total, 58 mutations were identified including 14 novel, previously unreported variants. Molecular characterization and identification of mutations have important implications for predictive, preventive, and personalized medicine, including genetic counseling and development of specific treatment protocols. We emphasize variants of unknown significance (VUS) as the clinical significance of VUS changes over time and variant classification is important for clinical molecular genetic testing and clinical guidance. This study may provide new insights into risk assessment for variants in CDH1, PALB2, PTEN and TP53, in addition to BRCA1 and BRCA2, which may prove useful for clinical management of breast cancer patients. Further studies are needed to identify the common gene variants in the Turkish population and evaluate the pathogenity of VUS.

Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients.

Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants.

A NEW MUTATION IN THE PALB2 GENE ASSOCIATED WITH HEREDITARY BREAST CANCER IN A YOUNG PATIENT BELONGING TO THE YAKUT ETHNIC GROUP

Breast cancer is the most common cancer worldwide. The oncosuppressor gene PALB2, along with such genes as BRCA1 and BRCA2, is involved in the repair of damaged DNA. The incidence of germline mutations in the PALB2 gene in breast cancer and in familial cases of pancreatic cancer is approximately 1–2% and 3–4%, respectively. A clinical case of a 39-year-old woman belonging to the Yakut ethnic group, diagnosed with breast cancer and with a family history of pancreatic cancer, is presented hereby.

Risk-reducing surgery in PALB2 mutations carriers with breast cancer: a case series and literature review.

Inherited germline mutations in PALB2 are known to predispose patients to a higher risk of breast, ovarian and pancreatic cancer with an estimated risk of developing breast cancer in over half of all affected women by age 80 years. Current guidelines for screening patients with PALB2 mutations include annual mammograms beginning at age 30 years and consideration of breast magnetic resonance imaging (MRI) and tomosynthesis. Existing evidence regarding risk-reducing surgery with mastectomy is insufficient to make a definitive recommendation to patients. In this case series, we describe the presentation and management of 5 patients with unilateral breast cancer and PALB2 mutations. To our knowledge, this is the first reported case series discussing the role of contralateral risk-reducing mastectomy (CRRM) in breast cancer patients with PALB2 mutations. The aim of our study was to evaluate the challenges in managing breast cancer risk in patients with PALB2 pathogenic variants with illustration through real-world clinical cases and a review of the literature. In this retrospective observational study, we present 5 patients with PALB2 mutations between the ages of 29 and 61 years who were diagnosed with breast cancer and underwent surgical management of their breast cancer at our institution between November 2020 and March 2022. Through their clinical courses and a literature review, we discuss the role of CRRM in breast cancer patients with PALB2 gene mutations. Out of the 5 patients, 3 patients underwent CRRM and 2 patients chose unilateral surgery for their breast cancer and active surveillance for the contralateral breast. Of the 3 patients who underwent CRRM, 1 patient experienced a surgical complication from reconstruction on the prophylactic side. None of the patients developed any recurrences with an average length of follow up of 15.4 months. Based on our experience and the currently available literature, CRRM in patients with a PALB2 mutation should be performed on a case-by-case basis through a shared decision-making process taking into consideration overall risk, family history, patient preference and quality of life.

Modulation of DNA Methylation/Demethylation Reactions Induced by Nutraceuticals and Pollutants of Exposome Can Promote a C > T Mutation in the Breast Cancer Predisposing Gene PALB2

Background: Deregulation of DNA methylation/demethylation reactions may be the source of C > T mutation via active deamination of 5-methylcytosine to thymine. Exposome, that is to say, the totality of exposures to which an individual is subjected during their life, can deregulate these reactions. Thus, one may wonder whether the exposome can induce C > T mutations in the breast cancer-predisposing gene PALB2. Methods: Our work is based on the exposure of MCF10A mammary epithelial cells to seven compounds of our exposome (folate, Diuron, glyphosate, PFOA, iron, zinc, and ascorbic acid) alone or in cocktail. The qMSRE and RMS techniques were used to study the impact of these exposures on the level of methylation and mutation of the PALB2 gene. Results: Here, we have found that exposome compounds (nutriments, ions, pollutants) promoting the cytosine methylation and the 5-methylcytosine deamination have the ability to promote a specific C > T mutation in the PALB2 gene. Interestingly, we also noted that the addition of exposome compounds promoting the TET-mediated conversion of 5-methylcytosine (Ascorbic acid and iron) abrogates the presence of C > T mutation in the PALB2 gene. Conclusions: Our study provides a proof of concept supporting the idea that exposomes can generate genetic mutation by affecting DNA methylation/demethylation.

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes.

Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3′ of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband’s mutation; of these, 24 developed cancer, with 41 remaining unaffected.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes

Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR)= 10.6] down to a population minor allele frequency of 4.6× 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR= 5.0) down to a population minor allele frequency of 2.8× 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR= 2-3) like CHEK2 and ATM. This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Clinical and prognostic characteristics of &lt;I&gt;BRCA1/2&lt;/I&gt;-associated breast cancer depending on the type of mutation: estrogen signaling pathway and secondary tumors

Background. Currently, there is growth evidence on prognostic and clinical differences in breast cancer (BC) associated with different types of BRCA1 / 2 mutations. At the same time, a triple negative tumor phenotype is not an absolute pathognomonic sign of BRCA1 / 2-associated cancer, where luminal phenotypes are being detected increasingly. In addition, attention is paid to the significance of estrogen signaling mechanism depending on the surrogate tumor type, including a triple negative phenotype due to alternative mechanisms.Objective: to evaluate significance of BRCA1 / 2-mutations in luminal BC subtypes and multiple tumors.Materials and methods. A prospective study conducted in Clinical Oncology Dispensary No. 1 in Krasnodar included 443 patients with breast cancer who underwent a genetic analysis on BRCA1 / 2 genes status by real-time polymerase chain reaction. In diagnostic cases of luminal phenotype and multiple cancers histological material and blood were sent to the N.N. Petrov Research Institute of Oncology of Ministry of Health of Russia to assess the mutation status of the BRCA1 / 2, ATM, CHEK2, NBS1, PALB2 genes by next-generation sequencing (NGS). Statistical analysis of clinical and morphological parameters correlated with mutational status was performed using the IBM SPSS Statistics v.22 statistical package.Results. An interim analysis of data in April 2022 showed that 71 out of 304 breast cancer patients tested by polymerase chain reaction were found to be carriers of BRCA1 gene mutations. NGS method revealed 20 additional mutations of the BRCA1 / 2 genes: 11 BRCA1 mutations and 9 BRCA2 mutations. PALB2 mutation was also detected in 1 patient, NBS1 mutation – in 3, CHEK2 mutation – in 2, ATM mutation – in 2 patients. Out of 91 BRCA1 / 2-associated breast cancer 21 BRCA1-mutated tumors and 9 tumors with BRCA2-mutation demonstrated luminal phenotypes. The median age of breast cancer disease did not differ in BRCA1- and BRCA2-carriers (42 years versus 40 years, p ˃0.05). BRCA1 mutations are associated with poor differentiation (G3), BRCA2 mutations are associated with G2 (p ˂0.001). The BRCA2 mutation is characterized by a luminal tumor phenotype (p ˂0.001). There was no association of BRCA1 / BRCA2 gene mutations with T and N status (p ˃0.05). Of the 91 cases of BRCA-deficient tumors, 30 (33 %) patients had primary multiple cancer: 27 (90 %) with germinal mutation BRCA1 and 3 (10 %) with germinal mutation BRCA2. Contralateral breast cancer in the presence of germinal mutation BRCA1 was detected in 14 patients. The frequency of primary multiple cancer and contralateral breast cancer detection did not depend on the type of BRCA1 / 2 mutations (p ˃0.05).Conclusion. With the primary multiplicity of the tumor process and the luminal subtype of the tumor, the determination of mutations by polymerase chain reaction in real time is clearly insufficient. It is obvious that the NGS method can identify additional pathogenic mutations that predict the clinical course and indicate the possibility of personalizing therapy and the need to test relatives, including tumors with luminal phenotype and tumors of several localizations.