Hereditary Malignancies Research Articles

The Crucial Role of Hereditary Cancer Panel Testing in Unaffected Individuals with a Strong Family History of Cancer: A Retrospective Study of a Cohort of 103 Healthy Subjects.

Hereditary cancer syndromes caused by germline mutations account for 5-10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network's (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status.

Abstract PO1-09-03: Clinical Impact of Multigene Panel Testing in Patients with a Personal or Family History of Breast or Ovarian Cancer Previously Negative for BRCA1/2 Genes

Abstract Rapid developments in cancer genetics and hereditary cancer risk assessments have enabled the identification of individuals at elevated risk for hereditary malignancies to guide enhanced cancer screening and prevention efforts. Multigene panel testing has emerged as the standard approach as emphasized in the National Comprehensive Cancer Network (NCCN) guidelines. The purpose of this study was to investigate the frequency of other pathogenic mutations identified through multigene panel testing in individuals who previously tested negative for germline BRCA1/2 and assess the clinical impact of panel testing. Patients either previously diagnosed with breast cancer or with a family history of breast or ovarian cancer that had also been seen by Oncology Genetics at a single institution and tested negative for BRCA1/2 genes but had not undergone prior multigene panel testing were invited via a letter to return for an additional genetic counseling visit to discuss multigene panel testing. Patients were also able to opt-in to a survey component of the study and received an email to fill out the Multidimensional Impact of Cancer Risk Assessment (MICRA) and Cancer Worry Scale (CWS). Surveys were completed prior to the initial genetic counseling appointment and repeated after discussion of the multigene panel test results. A total 24 women met with a genetic counselor of which 22 (92%) had a personal history of breast cancer, 1 (4%) had a family history of breast cancer, and 1 (4%) had a family history of ovarian cancer. The mean age was 52.6 years (range, 42-68) and 100% of women were Caucasian. Of the 24 women, 17 (71%) completed multigene panel testing. Of the women that underwent testing, 7 (41%) had negative results, 6 (35%) had variants of unknown significance (VUS), and 4 (24%) had a pathogenic mutation identified in another gene (CDKN2A, CHEK2, and CFTR). There was no significant change in MICRA or CWS scores after multigene panel results were reviewed in the 9 patients that completed both pre- and post-genetic testing surveys. The mean/median summary MICRA scores pre- and post-counselling were 30 (SD 12.4), median 26 (min 18, max 56), and 21.2 (SD 15.4), median 21 (min 3, max 43), respectively (p=0.19, Wilcoxon signed ranks test). The mean/median summary CWS scores pre- and post-counselling were 14.3 (SD 5), median 15 (min 7, max 24), and 13.6 (SD 2.59), median 14 (min 10, max 17), respectively (p=0.53, Wilcoxon signed ranks test). Of the 4 patients with newly identified pathogenic mutations, 2 started new screening protocols and 1 underwent a prophylactic mastectomy. In conclusion, multigene panel testing identified pathogenic mutations in a subset of individuals who previously tested negative for BRCA1/2 genes leading to changes in clinical management. The completion of multigene panel testing did not lead to a significant increase in MICRA or CWS scores. Key limitations of this study include a small sample size and an all Caucasian population. Citation Format: Devon Miller, Stephanie Pritzl, Angela Tess, Jessica Gooding, Lisa Barroilhet, Lori Dubenske, Kari Wisinski. Clinical Impact of Multigene Panel Testing in Patients with a Personal or Family History of Breast or Ovarian Cancer Previously Negative for BRCA1/2 Genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-03.

Machine learning based prediction of recurrence after curative resection for rectal cancer

Purpose Patients with rectal cancer without distant metastases are typically treated with radical surgery. Post curative resection, several factors can affect tumor recurrence. This study aimed to analyze factors related to rectal cancer recurrence after curative resection using different machine learning techniques. Methods Consecutive patients who underwent curative surgery for rectal cancer between 2004 and 2018 at Gil Medical Center were included. Patients with stage IV disease, colon cancer, anal cancer, other recurrent cancer, emergency surgery, or hereditary malignancies were excluded from the study. The Synthetic Minority Oversampling Technique with Tomek link (SMOTETomek) technique was used to compensate for data imbalance between recurrent and no-recurrent groups. Four machine learning methods, logistic regression (LR), support vector machine (SVM), random forest (RF), and Extreme gradient boosting (XGBoost), were used to identify significant factors. To overfit and improve the model performance, feature importance was calculated using the permutation importance technique. Results A total of 3320 patients were included in the study. After exclusion, the total sample size of the study was 961 patients. The median follow-up period was 60.8 months (range:1.2–192.4). The recurrence rate during follow-up was 13.2% (n = 127). After applying the SMOTETomek method, the number of patients in both groups, recurrent and non-recurrent group were equalized to 667 patients. After analyzing for 16 variables, the top eight ranked variables {pathologic Tumor stage (pT), sex, concurrent chemoradiotherapy, pathologic Node stage (pN), age, postoperative chemotherapy, pathologic Tumor-Node-Metastasis stage (pTNM), and perineural invasion} were selected based on the order of permutational importance. The highest area under the curve (AUC) was for the SVM method (0.831). The sensitivity, specificity, and accuracy were found to be 0.692, 0.814, and 0.798, respectively. The lowest AUC was obtained for the XGBoost method (0.804), with a sensitivity, specificity, and accuracy of 0.308, 0.928, and 0.845, respectively. The variable with highest importance was pT as assessed through SVM, RF, and XGBoost (0.06, 0.12, and 0.13, respectively), whereas pTNM had the highest importance when assessed by LR (0.05). Conclusions In the current study, SVM showed the best AUC, and the most influential factor across all machine learning methods except LR was found to be pT. The rectal cancer patients who have a high pT stage during postoperative follow-up are need to be more close surveillance.

Predictors of Multiple Primary Malignancies: Literature Review

The present paper considers the predictors of multiple primary malignancies. The multiple primary malignancies are often induced by genetic predisposition and familial cancer syndromes, environmental carcinogens and bad habits (e.g. tobacco and alcohol abuse), immunodeficiency and infectious diseases, carcinogens occurring as a result of various treatments, etc. Germinal mutations are considered to be one of the causes of primary cancer — they increase the risk of various multiple primary malignancies. Hereditary cancers are characterized by a strong family history, early age of onset and occurrence of multiple primary malignancies. The paper considers various mechanisms of multiple primary malignancies with an emphasis on the effect of carcinogens in carriers of pathogenic genes on cancer development. In proven cases, when patients are exposed to multiple carcinogens, they should be aware of possible late and long-term effects of treatment and their symptoms, as well as secondary malignancies that might occur. When the main predictors of carcinogenesis are manageable, and primary preventive measures can be taken, the hereditary malignancies require postexposure prophylaxis. In addition to specific recommendations for the prevention of primary cancers, it is essential to follow recommendations for the prevention of second primary cancers.

Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). All relevant information was collected about PC and APT patients treated between 2009 and 2021. Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Abstract 258: Whole genome analysis of hereditary leiomyomatosis and renal cell cancer identifies role of localized hypermutational events

Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare hereditary condition affecting over 1 in 200,000 people worldwide. Individuals with HLRCC are also at risk of developing an aggressive form of renal cell carcinoma (RCC), as 15-20% of patients develop type 2 papillary RCC associated with poor prognosis. Although RCC risk and cancer penetrance of this condition has been studied, whole genome sequencing of associated tumors has yet to be examined, and the landscape of structural variants of HLRCC is largely unknown. We have therefore performed whole genome sequencing of tumor/normal pairs of HLRCC patients to study the tumor molecular architecture in this form of RCC. Through germline variant and somatic mutation calling, we have identified specific somatic mutational drivers, including those at the structural variant level for the first time in HLRCC. We have also quantified both chromothripsis and kataegis in these tumors, identifying the specific role of localized hypermutational events. Similarly, using tumour subclonal reconstruction techniques, we have inferred the clonality of HLRCC-associated RCC tumors and elucidate the relative timing of key oncogenic events and mutational processes. We also compare each of these mutational features to their equivalents in other RCC tumour subtypes. These studies shed key light on the specific mutational processes and drivers of this rare hereditary malignancy and on its lethality. Citation Format: Selina Wu, Paul C. Boutros. Whole genome analysis of hereditary leiomyomatosis and renal cell cancer identifies role of localized hypermutational events [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 258.

Imaging Recommendations for Diagnosis, Staging, and Management of Hereditary Malignancies

AbstractHereditary cancer syndromes, characterized by genetically distinct neoplasms developing in specific organs in more than one family members, predispose an individual to early onset of distinct site-specific tumors. Early age of onset, multiorgan involvement, multiple and bilateral tumors, advanced disease at presentation, and aggressive tumor histology are few characteristic features of hereditary cancer syndromes. A multidisciplinary approach to hereditary cancers has led to a paradigm shift in the field of preventive oncology and precision medicine. Imaging plays a pivotal role in the screening, testing, and follow-up of individuals and their first- and second-degree relatives with hereditary cancers. In fact, a radiologist is often the first to apprise the clinician about the possibility of an underlying hereditary cancer syndrome based on pathognomonic imaging findings. This article focuses on the imaging spectrum of few common hereditary cancer syndromes with specific mention of the imaging features of associated common and uncommon tumors in each syndrome. The screening and surveillance recommendations for each condition with specific management approaches, in contrast to sporadic cases, have also been described.

Hereditary cancer syndromes.

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

Transcutaneous Tumor Vaccination Combined With aPD-1 Treatment Produces a Synergistic Antitumor Effect

Transcutaneous immunization (TCI) has the advantages of safety, high efficiency, non-invasiveness and convenient use. The basis for the realization of TCI is that skin tissue is rich in dendritic cells (DCs) which are the most powerful antigen presenting cells. DCs also play a key role in tumor immunotherapy, which provides a huge imagination for the application of TCI to tumor treatment. In this study, a novel transdermal tumor vaccine (TTV) delivery system was developed based on the electrospun silkfibroin-polyvinyl alcohol (SF-PVA) nanofibrous patch loaded with surface modified ethosome (Eth). Mannosylated PEI (PEIman) was used to modify Eth, giving the new carrier (termed Eth-PEIman) the ability to simultaneously load polypeptide antigens and oligonucleotide adjuvants and transdermal targeted DCs delivery. With TRP2 peptide as antigen (encapsulated in Eths) and oligodeoxynucleotides containing unmethylated CpG motifs (absorbed in PEIman) as adjuvant, the TTV-loaded patches (TTVP) significantly inhibited the growth of melanoma in mouse model. Moreover, the combined application of the TTVP and anti-programmed death-1 monoclonal antibody (aPD-1) produced a synergistic anti-tumor effect, resulting in a much stronger anti-tumor effect, which may be due to the infiltration of more CD4+ and CD8+ T cells in the tumor tissues. The application of TTVP also increased the expression of IL-12, which may be part of the mechanism of synergistic anti-tumor effect between the TTVP and aPD-1. These results suggest that the combination of the TTVP and immune checkpoint blockers could be an effective strategy for tumor treatment. Our work provides a noninvasive and convenient way for improving the efficacy of immune checkpoint blocking therapy as well as prevention of some family hereditary malignancies.

MALIGNANT MESOTHELIOMA AND GERMLINE HETEROZYGOUS BAP1 MUTATION IN A YOUNG WOMAN PRESENTING WITH RECURRENT PLEURAL EFFUSIONS AND WORSENING PNEUMOTHORAX AFTER TALC PLEURODESIS

SESSION TITLE: Fellows Lung Cancer Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Germline BAP1 mutations are associated with a pattern of hereditary malignancies, namely uveal and cutaneous melanoma, malignant mesothelioma (MM), and renal cell carcinoma. We present a rare case of a young woman who was diagnosed with malignant pleural and peritoneal mesothelioma. CASE PRESENTATION: A 23 year-old woman with no known medical conditions or exposure to asbestos was referred to medical oncology after completing a video-assisted thoracoscopic surgery (VATS) followed by talc pleurodesis for recurrent pleural effusions of unknown etiology. Initial pleural fluid studies showed total protein 4.5 g/dL and LDH 150 U/L. Pleural fluid contained clusters of atypical mesothelial cells surrounded by inflammation suggestive of reactive mesothelial hyperplasia. VATS found abnormal reticulated surfaces and a white plaque-like tissue at the apex. Pleural biopsies showed atypical mesothelial proliferation suspicious for MM in a background of reactive changes, but ultimately results were considered non-diagnostic. Due to inconclusive pathology we recommended further evaluation with diagnostic laparoscopy because her CT scans also showed small volume ascites and pelvic fluid. Studding was noted on peritoneum, bowel, pelvic tissues, and omentum, and biopsies showed markedly atypical proliferation of epithelioid cells forming glandular and tubulopapillary structures with disorganized growth and focal invasion into adjacent adipose tissue. Immunostains of tumor cells were consistent with mesothelial differentiation. BAP-1 immunohistochemistry showed loss of expression only in tumor cells. Collectively these features supported a diagnosis of MM of epithelioid type. Peripheral blood testing for BAP1 tumor predisposition syndrome (BAP1-TPDS) was positive for a heterozygous germline BAP1 mutation, c.2050 C>T, p.Gln684* (Pilarski et al. 2013, Haugh et al. 2017). Staging scans prior to chemotherapy showed interval development of a pneumothorax in the right lung months after her talc pleurodesis. She was treated with cisplatin, pemetrexed, and bevacizumab with subsequent improvement of her pneumothorax. DISCUSSION: Our case report showed the clinical features of a patient with MM from BAP1-TPDS. Loss of BAP1 expression can help distinguish MM from reactive mesothelial cells (Cigognetti et al. 2015). Progression of her disease after having a talc pleurodesis manifested radiographically as a worsening pneumothorax, and chemotherapy was able to reverse this process. CONCLUSIONS: Unexplained pleural effusions or pleural or peritoneal biopsies showing atypical mesothelial cells should have immunohistochemistry testing for loss of BAP1 expression to evaluate for MM. MM due to BAP1-TPDS is responsive chemotherapy. Young MM patients without risk factors for MM should have germline testing for BAP1-TPDS. Reference #1: Pilarski, Robert, et al. “Expanding the Clinical Phenotype of hereditaryBAP1cancer Predisposition Syndrome, Reporting Three New Cases.” Genes, Chromosomes and Cancer, vol. 53, no. 2, 15 Nov. 2013, pp. 177–182., doi:10.1002/gcc.22129. Reference #2: Haugh, Alexandra M., et al. “Genotypic and Phenotypic Features of BAP1 Cancer Syndrome.” JAMA Dermatology, vol. 153, no. 10, 9 Aug. 2017, p. 999-1006., doi:10.1001/jamadermatol.2017.2330. Reference #3: Cigognetti, Marta, et al. “BAP1 (BRCA1-Associated Protein 1) Is a Highly Specific Marker for Differentiating Mesothelioma from Reactive Mesothelial Proliferations.” Modern Pathology, vol. 28, no. 8, 29 May 2015, pp. 1043–1057., doi:10.1038/modpathol.2015.65. DISCLOSURES: Speaker/Speaker's Bureau relationship with Daiichi Sankyo/AstraZeneca Please note: $1-$1000 Added 03/18/2020 by Blakely Kute, source=Web Response, value=Honoraria No relevant relationships by Eric Luk, source=Web Response

The chairs of hereditary cancer: understanding time and illness using creative ethnographic drawing

Using scientific illustration, this article aims to examine how time is experienced, understood, and managed in hereditary malignancies, analysing the breast cancer story of a Portuguese woman with BRCA1/2 mutations. Blending lived experience, anthropology, and art, this text results from a transdisciplinary qualitative exercise, incorporating embodied knowledge, speech, and creative ethnographic drawing at the core of the research, using them as methodological and heuristic resources. Based on a narrative collected in an informal interview, it suggests the use of visual and creative methodologies aimed at a reinforced understanding of cancer. Combining text and images, we will analyse the multiple meanings of time that permeate this story, searching for the experiences, uses, and meanings of moments of waiting, interruption, slowness, delay, urgency, and acceleration, before, during and after illness and treatment, using and drawing chairs, as concrete objects and metaphors, to give them form. Waiting emerges as the most relevant experience to understand her hereditary cancer story, linking past, present, and future within a form of suffering that minimizes physical pain.

Disparities in genetics assessment for women with ovarian cancer: Can we do better?

ObjectiveWe sought to characterize referral patterns for genetic counseling for women with ovarian cancer and hypothesized that differences in referral and testing rates are shaped by socioeconomic factors. MethodsPatients were identified by pathology reports from August 2012 to January 2016 containing the words “serous” or “ovarian.” Patient information was obtained via electronic medical record. Primary outcomes were placement of a genetics referral and completion of counseling. A secondary outcome was completion of genetic testing. ResultsWe identified 246 women with a diagnosis of ovarian cancer. Ten were previously counseled and excluded. 53% of patients were referred for counseling with mean time from diagnosis to counseling of 4.6months. Age and family history were not associated with referral, however rates differed by race with 61% of Caucasian and 40%, 38% and 33% of Asian, Latina and Black women, respectively, referred (p=0.035). Overall, 36% of patients diagnosed underwent counseling, and 33% were tested. English language (p<0.0001), high-grade serous histology (p=<0.0001) and private or Medicare insurance (p<0.0001) were significantly associated with referral. ConclusionWe have not yet reached the Society of Gynecologic Oncology recommendation for referral to genetics. Women of color and those with public insurance have lower referral rates. This disparity in care impacts cancer treatment options and prevents appropriate screening for other hereditary malignancies. To provide comprehensive oncology care, including genetic assessment, we recommend focusing on these barriers including improving outreach and interpreter services.

A new strategy for prophylactic surgery in BRCA women: Combined mastectomy and laparoscopic salpingo-oophorectomy with immediate reconstruction by double DIEP flap

Prophylactic surgery remains the most effective modality for reducing both breast and ovarian cancer rate in woman at high risk, such as BRCA1 or BRCA2. Autologous breast reconstruction with bilateral deep inferior epigastric perforator (DIEP) flap allows predictable and durable results. However, existing two-step approach separating salpingo-oophorectomy and reconstruction could even make DIEP flap impossible, or make insufflation more difficult during laparoscopy. Other authors described one-step procedure but with open laparotomy. The goal of this study was to verify the feasibility of a simultaneous procedure, including laparoscopic salpingo-oophorectomy. We included BRCA mutation careers scheduled for simultaneous laparoscopic salpingo-oophorectomy, and bilateral breast reconstruction with DIEP flaps. The first step of the procedure was laparoscopic salpingo-oophorectomy and ports had to be strategically placed to avoid interference with the following procedure. The second step was bilateral breast reconstruction with DIEP flaps. We reviewed medical charts. Surgical procedure was analyzed for duration, revisions and surgical complications. During 1-year period, eight patients agreed to a simultaneous procedure. All of them were BRCA positive, mean age was 38.3years (range, 39-50), and mean BMI was 28.3kg/m(2) (range, 21-33). The mean duration of the entire procedure was 524minutes (range, 405-630) and the mean hospital stay 9.2 days (range, 8-14). There was 100% flap survival. No abdominal wall dehiscence occurred. One-step procedure for prophylactic surgery of ovarian and breast hereditary malignancies is feasible. First salpingo-oophorectomy with open laparoscopy then bilateral immediate or delayed breast reconstruction with DIEP flaps can be performed.

Genetic polymorphisms and ovarian cancer risk and response to paclitaxel/cisplatin chemotherapy

Single nucleotide polymorphisms modulate the risk of developing ovarian cancer during lifetime. In this study we analyzed 12 polymorphic variants and 2 deletions in PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes. Ten genetic modifications were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. PGR gene polymorphisms’ impact on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers, which proves the difference in the modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in three out of four groups. Cumulative risk analysis revealed 3 unfavorable variants that significantly increased the risk of developing ovarian cancer, and also two favorable genotypes which protected against ovarian cancer. Survival analysis for carriers of favorable versus unfavorable genotypes emphasized the importance of regulation of the cell cycle and active transport of xenobiotics during paclitaxel/cisplatin chemotherapy. The unfavorable variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.

Genetic polymorphisms and gene-dosage effect in ovarian cancer risk and response to paclitaxel/cisplatin chemotherapy.

BackgroundOvarian malignancies are often diagnosed in advanced stage and at the same time resistance to treatment, both intrinsic and developed during treatment, is sometimes observed. These facts underscore the need for new markers of ovarian cancer risk, as well as markers of treatment effectiveness.MethodsIn this study we genotyped 225 ovarian cancer patients, 64 breast and ovarian cancer patients and 348 healthy controls. In total, 12 polymorphic variants and 2 deletions in PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes were analyzed using ASA-PCR, RFLP-PCR, multiplex-PCR and sequencing.ResultsTen genetic polymorphisms were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. Impact of PGR gene polymorphisms on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers (in presence of p.Val660Leu variant- OR 2,82; p = 0,010), which confirms the difference in modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in all groups excluding the group with BRCA1 mutation. Cumulative risk analysis revealed 3 unfavorable variants that increased significantly the risk of developing ovarian cancer (p.Ile1145 = ABCB1+ p.Asp1853Asn ATM+ p.Ser406Ala ATP7B- OR 7,47; p = 0,002) and significantly modified the progression free survival (PFS) of the patients, and also two favorable genotypes which protected against ovarian cancer (p.Arg952Lys ATP7B+ p.Arg72Pro TP53- OR 0,50; p = 0,008). PFS analysis for carriers of favorable versus unfavorable genotypes emphasized the impact of the regulation of cell cycle (p.Asp1853Asn ATM) and active transport of xenobiotics (p.Ser894Ala/Thr ABCB1) on the risk of disease progression (HR 3,81; p = 0,010) after paclitaxel/cisplatin chemotherapy.ConclusionsThe unfavorable genetic variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.

The Upgrade of Hereditary Cancer Surveillance Schedule by Valka District Population Screening Data

The Upgrade of Hereditary Cancer Surveillance Schedule by Valka District Population Screening Data Introduction. The concept of hereditary cancer is one of the most important achievements in modern oncology. It has major scientific implications as well as high practical value in surveillance, prevention and adjustment of treatment for hereditary and familial malignancies. Identification of the persons-at-risk allows recommending a follow-up schedule for timely diagnostics of the corresponding cancers. Aim of the Study is to evaluate the need for hereditary cancer surveillance program in Latvia and to adjust the surveillance schedule by population screening data. Materials and methods. The study was performed as population screening in the Valka district, evaluating the family cancer history of 18642 respondents. Hereditary cancers were diagnosed by internationally accepted clinical criteria. Descriptive statistical analysis was carried out by CIA software. Results. There were 885 persons, fulfilling the clinical diagnostic criteria of hereditary and familial cancer syndromes. The full spectrum of hereditary malignancies was identified thus indirectly characterising the familial background of oncological diseases in the local population. The cancer burden among blood relatives was high for all syndromes, exceeding 8.6%. The mean age of cancer diagnostics was significantly different among the syndromes, ranging 38.0-72.0 years. Conclusions. The presence of familial background in all most frequent cancer locations and the high cancer burden in the affected kindreds justify the need for familial cancer surveillance. The data about the age of cancer manifestation can be used to adjust the follow-up schedule for most syndromes. Specific recommendations are elaborated and described in the article.

Combined effects of MDM2 SNP 309 and p53 mutation on oral squamous cell carcinomas associated with areca quid chewing

The recently identified single nucleotide polymorphism in the MDM2 promoter (SNP 309) may contribute to the early onset of both sporadic and hereditary malignancies in patients with defective p53. We tested this hypothesis by examining the effects of combined MDM2 polymorphisms and somatic p53 mutations on 351 oral squamous cell carcinomas (OSCCs) associated with areca quid chewing. We found that the G allele of MDM2 SNP 309 was associated with early age of onset (p=0.02) and poor differentiation of OSCC tumors (p=0.01). The frequency of lymph node extracapsular spread (LNECS) was increased in individuals having both the MDM2 SNP 309 GG genotype and p53 mutation (chi(2) for trend p=0.04). MDM2 GG genotype and p53 mutations were associated with poor disease-free survival in both early and lymph node positive advanced stage OSCC patients (Hazard ratio=2.77 and 1.93, respectively). Taken together, an interaction between MDM2 SNP 309 and p53 with respect to tumor behaviors (including disease onset, tumor differentiation, LNECS and disease-free survival) was observed in sporadic Taiwanese OSCCs.

The Role of Prophylactic Surgery in Cancer Prevention

Since the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that "prophylactic surgery" would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by "prophylactic surgery." In this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.

Analysis of microsatellite instability and loss of heterozygosity in breast cancer with the use of a well characterized multiplex system.

Analysis of microsatellite instability (MI) and loss of heterozygosity (LOH) is recommended for screening patients with sporadic and hereditary malignancies. This study shows an application of a fluorescent hexaplex PCR system for microsatellite typing on A.L.F. DNA Sequencer (Pharmacia Biotech). This technique detects changes in microsatellites providing a time-efficient, reliable and accurate method for MI and LOH analyses. The Fragment Manager software was used for automated size calculation and quantitation of DNA fragments, enabling rapid and precise measurement of allelic ratios. We examined 70 breast cancer and 70 control DNA specimens, classified all the patterns of microsatellite alterations, and set up MI and LOH assessment criteria for the automated multiplex fluorescent method.

Analysis of microsatellite instability and loss of heterozygosity in breast cancer with the use of a well characterized multiplex system.

Analysis of microsatellite instability (MI) and loss of heterozygosity (LOH) is recommended for screening patients with sporadic and hereditary malignancies. This study shows an application of a fluorescent hexaplex PCR system for microsatellite typing on A.L.F. DNA Sequencer (Pharmacia Biotech). This technique detects changes in microsatellites providing a time-efficient, reliable and accurate method for MI and LOH analyses. The Fragment Manager software was used for automated size calculation and quantitation of DNA fragments, enabling rapid and precise measurement of allelic ratios. We examined 70 breast cancer and 70 control DNA specimens, classified all the patterns of microsatellite alterations, and set up MI and LOH assessment criteria for the automated multiplex fluorescent method.