Precision Therapy for Brain Tumors in Hereditary Syndromes.

OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.

Lynch Syndrome in Thai Endometrial Cancer Patients.

BACKGROUND: Lynch syndrome increases lifetime risk of endometrial cancer to 40-60%. Screening with molecular tumor testing for mismatch repair (MMR) proteins have been recommended. This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients. METHODS: Immunohistochemistry for MMR proteins, including MLH1, MSH2, MSH6 and PMS2 were tested in 166 surgical specimens. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel next generation sequencing. RESULTS: Fifty-eight of 166 patients (34.9%) had one or more MMR deficiencies which were: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). Of the 40 patients (24.1%) who met the revised Bethesda guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda guidelines. A total of 27 patients with MMR deficiencies agreed to have germline genetic testing. Germline MMR mutations were detected in 5 patients (18.5%) including MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Incidental germline mutations in other genes were detected in 3 patients (1 BRCA1, 1 PTEN, and 1 BARD1). Among 5 Lynch syndrome patients, 2 patients (40%) did not meet the revised Bethesda guidelines. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected. CONCLUSION: MMR deficiencies were detected in 34.9% of the endometrial cancer patients. Germline mutations were diagnosed in 3.0% of this cohort (5/166 patients). Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers.

PD­L1 and IDO­1 expression in undifferentiated pleomorphic sarcoma: The associations with tumor infiltrating lymphocytes, dMMR and HLA class I.

The prognosis of undifferentiated pleomorphic sarcoma (UPS) is generally unfavorable. Recently, clinical trials such as SARC028 demonstrated the utility of cancer immunotherapy for soft tissue sarcomas. The aim of the present study was to assess the expression of PD­L1 and IDO­1 as prognostic factors and therapeutic targets. A total of 52 primary UPS cases were retrieved and two UPS cell lines were utilized for supplementary analysis. Immunohistochemical staining of anti­PD­L1 (28­8), IDO­1, CD8, CD4, CD3, HLA class I, MSH2, MSH6, MLH1 and PMS2 was carried out. Immunohistochemically, 19 of 52 (36.5%) cases showed PD­L1 expression at least focally (≥1%) and 5 of 52 (9.62%) showed strong PD­L1 expression (≥50%). Overall, 25 of 52 (48.1%) cases expressed IDO­1 (≥1%). Two tumors were evaluated as having deficient mismatch repair and six tumors as having the loss of HLA class I. PD­L1 expression (≥1%) was significantly related to the infiltration of CD8­ and CD3­positive lymphocytes, but strong PD­L1 expression (≥50%) did not present a significant relationship with tumor­infiltrating lymphocytes. IDO­1 expression was also associated with CD8­, CD4­, and CD3­positive lymphocytes. In vitro, both PD­L1 and IDO­1 were induced by IFN­Î³ stimulation. In survival analysis, strong PD­L1 expression (≥50%) was a significant poor prognostic factor, while IDO­1 expression (≥1%) was a favorable one. In conclusion, UPS was shown to frequently express PD­L1 and IDO­1. It was suggested that PD­L1 expression (≥50%) and IDO­1 expression are poor and favorable prognostic factors of UPS patients, respectively.

Can we clinically identify patients at risk of malignant transformation of skin tumors in Brooke-Spiegler syndrome?

Brooke-Spiegler syndrome (BSS) is a rare inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms. BSS has been linked to mutations in CYLD gene, which is a tumor suppressor gene located on chromosome 16q12-q13. An increased risk of malignant transformation of adnexal cutaneous tumors in BSS patients has been reported. However, no reported genetic markers identify patients at risk of cutaneous malignancy. This study reviews published cases of BSS to investigate the role of clinical parameters as biomarkers of skin malignancy. A comprehensive review of the clinical aspects of BSS is based on 55 case reports. Our analysis revealed only age as a predictor of malignancy; however, this is also a general risk factor for development of malignancy and therefore of limited value as a screening tool. The study highlights the need for standardized clinical follow-up of patients.

A novel CDKN2A in-frame deletion associated with pancreatic cancer-melanoma syndrome.

Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.

HPV nonrelated endocervical adenocarcinoma in hereditary cancer syndromes.

INTRODUCTION: The relationship between endocervical cancer and cancer susceptibility syndromes is not yet fully understood. We present 2 cases of endocervical cancer: 1 arising in a patient carrier with a pathogenic BRCA1 variant and the second detected in a Lynch syndrome family carrying the MSH2 germline pathogenic variant. CASE DESCRIPTION: Somatic analyses including loss of heterozygosity and fluorescent in situ hybridization demonstrated that the second hit in patient 1 is BRCA1-related. Mismatch repair somatic analyses in the second family demonstrated that the endocervical cancers of patient 2 and of her sister are MSH2-related. These data confirm the relationship between the pathogenesis of endocervical cancer and the presence of germline BRCA1 and MSH2 mutations. CONCLUSIONS: Our study confirms that gynecologic cancers including rare entities such as non-human papillomavirus-related endocervical cancer (NHPVA) are sentinels for inherited cancer syndromes. Endocervical cancer NHPVAs might be considered for cancer genetic counseling in order to improve cancer prevention. For this reason, the role of pathologists is particularly important for the correct identification of the cervical tumor site.

Hereditary Syndromes in Neuroendocrine Tumors.

OPINION STATEMENT: Oncologists should be able to discern the salient clinical features of the most common germline mutations that give rise to neuroendocrine tumors. Astute recognition of an index patient affected by a hereditary syndrome can lead to a "tip-of-the-iceberg" phenomenon whereby their entire kindred can then be proactively monitored and managed potentially with substantial reduction of morbidity and mortality. Through careful history-taking, as well as thoughtful assimilation of findings from the physical exam, biochemical laboratories, scans, and pathology reports, the clinician can spot phenotypic clues that distinguish these familial patterns from sporadic cases of tumorigenesis.

Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant predisposition to hamartomatous polyps within the gastrointestinal tract, at high risk for malignant transformation. BMPR1A and SMAD4 loss-of-function variants account for 50% of the cases. More specifically, point mutations and structural abnormalities in BMPR1A lead to a highly penetrant yet variable phenotype of JPS. Intriguingly, in the developmental disorder caused by a recurrent 10q22.3q23.1 7 Mb deletion which includes BMPR1A, juvenile polyps have never been reported. We present the case of a young adult harboring this recurrent deletion, in a context of intellectual disability, ventricular septal defect and severe juvenile polyposis syndrome diagnosed at the age of 25 years, requiring a surgical preventive colectomy. She developed a gastric adenocarcinoma from which she died at the age of 32. We hypothesize that with the current available pangenomic CNV arrays, the diagnosis of 10q22.3q23.1 deletion is often made several years before the onset of the digestive phenotype, which could explain the absence of reports for juvenile polyps. This observation highlights the importance of an active digestive surveillance of patients with 10q22.3q23.1 deletion.

Familial aggregation of early-onset cancers.

This registry-linkage study evaluates familial aggregation of cancer among relatives of a population-based series of early-onset (≤40 years) cancer patients in Finland. A cohort of 376,762 relatives of early-onset cancer patients diagnosed between 1970 and 2012 in 40,538 families was identified. Familial aggregation of early-onset breast, colorectal, brain and other central nervous system (CNS) cancer and melanoma was explored by standardized incidence ratios (SIR), stratified by relatedness. Gender-, age- and period-specific population cancer incidences were used as reference. Cumulative risks for siblings and offspring of the proband up to age ≤40 years were also estimated. Almost all early-onset cancers were sporadic (98% or more). Among first-degree relatives, SIR was largest in colorectal cancer (14, 95% confidence interval 9.72-18), and lowest in melanoma (1.93, 1.05-3.23). Highest relative-specific SIRs were observed for siblings in families, where also parent had concordant cancer, 90 (43-165) for colorectal cancer and 29 (11-64) for CNS cancer. In spouses, all SIRs were at population level. Cumulative risk of colorectal cancer by age 41 was 0.98% in siblings and 0.10% in population, while in breast cancer the corresponding risks were 2.05% and 0.56%. In conclusion, early-onset cancers are mainly sporadic. Findings support high familial aggregation in early-onset colorectal and CNS cancers. Familial aggregation in multiplex families with CNS cancers was mainly attributed to neurofibromatosis and in colorectal cancer to FAP- and HNPCC-syndromes. The pattern of familial aggregation of early-onset breast cancer could be seen to support very early exposure to environmental factors and/or rare genetic factors.

Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.

Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations.

CONTEXT.­: Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (APC), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP. OBJECTIVE.­: To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification. DATA SOURCES.­: This review will be based on peer-reviewed literature and the authors' experiences. CONCLUSIONS.­: In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.

Modeling malignancies using induced pluripotent stem cells: from chronic myeloid leukemia to hereditary cancers.

Over the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate induced pluripotent stem cells (iPSCs) from several types of primary CML cells and to generate progenitors and differentiated cells with variable efficiency. Although these experiments have brought some new insights in the understanding of CML pathophysiology, the ultimate goal of generating induced leukemic stem cells (LSCs) with long-term multilineage potential has not yet been demonstrated. Experiments under way will determine whether additional signaling events are required to induce the emergence of bona fide LSCs. However, iPSC modeling offers the unique possibility to generate pluripotent cells harboring cancer-predisposing mutations using patient-derived noncancerous cells, as has been shown in Li-Fraumeni syndrome, BRCA-1 associated breast carcinomas, or RET-mutated medullary thyroid carcinomas. In these conditions, mutated iPSCs can then be used to study the mutational history that precedes the appearance of the malignant transformation and to develop novel drug-screening strategies. The ability to induce a successful differentiation program toward the tissue in which a given cancer develops or to generate tissue-specific cancer organoids in which the full oncogenic potential can be revealed remains a major challenge in the field. Similarly, in hematological malignancies, a significant hurdle remains due to the lack of adequate technology to induce the emergence of leukemic cells that resemble LSCs, which hinders our ability to study the mechanisms of therapy resistance.

Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma.

: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH-/- PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed "q-oxPTPome," a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by >10×. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTPs were those with relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathologic PTP oxidation and neoplastic disease. SIGNIFICANCE: This work identifies a novel mechanism of activation of the oncogenic kinase ABL1 via ROS-induced, oxidation-mediated inactivation of cognate protein tyrosine phosphatases.

Trichoepithelioma: A Comprehensive Review.

Trichoepithelioma is an uncommon benign adnexal neoplasm. It can present as a solitary non-familial or multiple familial form. Trichoepithelioma usually develops in early childhood or puberty. Females are more affected. It is attributed to two genetic mutations on chromosomes 9p21 and 16q12-q13. Multiple familial trichoepithelioma is an autosomal-dominant disorder, characterized by numerous nodules and papules, predominantly on the face and occasionally on the scalp, neck, or upper trunk, positive family history, and histopathological findings. The lesions gradually increase in both size and number over time; however, they remain mostly asymptomatic. Although it is rare, trichoepithelioma lesions can undergo malignant transformation to trichoblastic carcinoma or basal cell carcinoma. Patients mainly seek treatment because the lesions are usually disfiguring and can lead to psycho-social issues. Non-pharmacologic approaches (e.g., excisional surgery, laser resurfacing), as the current mainstay of management, suffer from several drawbacks. New treatment techniques such as pharmacotherapy with potentially effective agents deserve more attention and investigation.

Sebaceous Carcinoma: A Review of the Scientific Literature.

OPINION STATEMENT: Sebaceous carcinoma is a rare and potentially aggressive cutaneous malignancy. Commonly reported in the periocular area and the head and neck region, sebaceous carcinoma can arise from any sebaceous gland in the skin. The clinical presentation may be nonspecific, and a biopsy is important to establish a diagnosis and to differentiate from mimickers including benign sebaceous neoplasms, other adnexal tumors, and basal cell carcinoma. A diagnosis of Muir Torre syndrome should be considered in patients presenting with a sebaceous neoplasm. Early treatment is important given the potential of sebaceous carcinoma to spread to the regional lymph nodes and beyond. Sentinel lymph node biopsy and imaging to complete tumor staging may be indicated for larger or more aggressive tumors. Surgery, including Mohs micrographic surgery, remains the primary treatment modality for sebaceous carcinoma. Mohs micrographic surgery has the advantage of complete margin evaluation and low recurrence rates. Advanced cases may be treated with orbital exenteration, radiation therapy, chemotherapy, or combination therapy.

High-energy particle beam and gamma radiation exposure, familial relatedness and cancer in mice.

BACKGROUND: Some highly penetrant familial cancer syndromes exhibit elevated leukaemia risk, and there is evidence for familial clustering of lung cancer and other common cancers. Lung cancer and leukaemia are strongly radiogenic, but there are few indications that high-energy beam irradiation is markedly more effective than lower-energy radiation. METHODS: We used a Cox model with familially structured random effects to assess 16 mortality end points in a group of 1850 mice in 47 families maintained in a circular-breeding scheme, exposed to accelerated Si or Fe ions (0.4 Gy) or 137Cs gamma rays (3 Gy). RESULTS: There is periodicity in the effect of familial relatedness, which is most pronounced for pulmonary adenoma, Harderian-gland adenoma, Harderian-gland tumour, ectodermal tumour, pulmonary adenocarcinoma and hepatocellular carcinoma (P=0.0001/0.0003/0.0017/0.0035/0.0257/0.0340, respectively) with families that are 3-4 generations apart most strongly correlated; myeloid leukaemia also exhibited a striking periodic correlation structure. The relative risks of high-energy Si or Fe ions are not significantly different and are less than for 137Cs gamma-rays for most end points at the doses used. CONCLUSIONS: There is periodicity in the effect of familial relatedness for various cancer sites. The effects per unit dose of high-energy charged particle beams are no higher than ninefold those of lower-energy gamma radiation.

Hereditary leiomyomatosis and renal cell cancer syndrome: identification and clinical characterization of a novel mutation in the FH gene in a Colombian family.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC) is a rare disease and since the first report, it has been found in just over 200 families approximately, around the world (Smit et al. in Clin Genet 79:49-59, 2009). Patients in Colombia or in Latin America have not been described, as far as we know. HLRCC is inherited in an autosomal dominant manner, and it is caused by heterozygous germline mutations in the FH gene, which encodes the fumarate hydratase enzyme. It is characterized mainly by the appearance of cutaneous and uterine leiomyomas, and an early-onset, aggressive form of type 2- papillary renal cell carcinoma (Smit et al. in Clin Genet 79:49-59, 2009; Schmidt and Linehan in Int J Nephrol Renovasc Dis 7:253-260, 2014]. We report a Colombian family with HLRCC syndrome, with a novel mutation in FH gene (c.1349_1352delATGA) in which cutaneous leiomyomas have not been found, but other clinical manifestations such as type 2- papillary renal cell carcinoma, uterine leiomyomas and rare tumors were present. This investigation constitutes the first report of HLRCC syndrome in Colombia, and probably in Latin America.

MSI detection and its pitfalls in CMMRD syndrome in a family with a bi-allelic MLH1 mutation.

The constitutional MisMatch Repair deficiency (CMMRD) syndrome is one of the inherited cancer predisposition syndromes. More than two-third patients belonging to a CMMRD family are diagnosed mainly in the first decade with brain cancers and/or hematological malignancies. This syndrome is due to bi-allelic germline mutations in genes of the MMR pathway (MLH1, MSH2, MSH6 or PMS2). Our family report begins with the index case presenting initially with a medulloblastoma, which was even the two relapses in complete remission, when she was diagnosed for an AML. She died after bone marrow transplantation from toxicity. The family history was progressively established when her uncle was diagnosed for a colonic cancer and a cousin for a brain tumor. Surprisingly, her father had an atypical sarcoma but her brother also presented a lymphoma followed by a gliomatosis cerebri. A new MLH1 bi-allelic mutation was identified in this family. More than the diagnostic difficulties, this family report illustrates the complexity of the microsatellite instability detection in CMMRD patients, which has to be discussed further to a more accurate diagnosis in the pediatric setting, and address the question of the proper diagnostic tool to use in such genetic background with hypermutated tumors.

CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models.

CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice.