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Hereditary cancer syndromes are inherited pathogenic genetic variants that significantly increase the risk of developing cancer. When individuals become aware of their increased probabil-ity of having cancer, the whole family is affected by this new reality and needs to adjust. However, adjustment to hereditary cancer syndromes has been mainly studied at an individual level, and research about familial adjustment remains dispersed and disorganized. To overcome this gap, this review aims to understand how families adjust to genetic testing and risk management, and to what extent the family’s adjustment influences the psychological response and risk management behav-iors of mutation carriers. We conducted searches on the PubMed/Med Line, PsycInfo, SCOPUS, and Google Scholar databases and used the Mixed Methods Appraisal Tool (MMAT-v2018) to assess the methodological quality of each selected study. Thirty studies met the inclusion criteria. Most results highlighted the interdependent nature of adjustment of pathogenic variant carriers and their fami-lies. The way carriers adjust to the syndrome is highly related to how family members react, partic-ularly partners and siblings dependent on prior family functioning. Couples who share their wor-ries and communicate openly about cancer risk present a better long-term adjustment than couples who use protective buffering (not talking about it to avoid disturbing the partner) or emotional distancing. Parents need help dealing with disclosing genetic information to their children. These findings reinforce the importance of adopting a family-centered approach in the context of genetic counseling and the necessity of involving family members in research.

While hereditary cancer syndromes have been described and studied for centuries, the completion of the human genome project fueled accelerated progress in precision medicine due to the introduction of genetic testing in the 1990s, creating avenues for tailored treatments and medical management options. However, genetic testing has not benefited everyone equitably, with nearly all of the published work based on individuals of non-Hispanic White/European ancestry. There remains a gap in knowledge regarding the prevalence, penetrance, and manifestations of common hereditary cancer syndromes in the African-American population due to significant disparities in access and uptake of genetic testing. This review summarizes the available literature on genetic testing for breast, colon, and prostate cancers in the African-American population and explores the disparities in access to genetic testing between non-Hispanic White and African-American patients. This article also addresses the barriers to genetic testing and discrepancies in the uptake of recommendations for hereditary cancer syndromes in the African-American population when compared with non-Hispanic Whites. The review offers practice implications for many healthcare providers and demonstrates gaps in the existing knowledge to be addressed in future studies to help eliminate the persisting health disparities faced by the African-American population.

Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of gra

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Estimates of the number of childhood cancers with a genetic basis range from 5–8.5% found in germline samples to 29% based on clinical criteria. Family history-taking practice is a fundamental first step in detecting at risk individuals and families. This study focused on Li-Fraumeni Syndrome (LFS), a highly penetrant cancer syndrome. Reported family history in a cohort of 648 of cancer survivor cohort (CCS) was examined. Eligible CCS were: (i) aged up to 14 years at diagnosis; (ii) more than 5 years postdiagnosis; (iii) treated for a childhood cancer at the study hospitals in NSW, Australia; (iv) in remission for more than 3 years. CCS completed self-administered questionnaires. Medical records confirmed diagnosis and treatment-related information. Our findings reveal an increased cancer risk among sibling and relatives of CCS. 91% of siblings diagnosed with cancer were diagnosed under the age of 40 and about 30% diagnosed under the aged of 15 revealing a 5- (RR = 5.1; 95% CI, 3.3–7.9) and 44-fold (RR = 44.6; 95% CI, 18.4–108.3) increased risked of cancer compared with the Australian population, respectively. About 2% of CCS reported that they had been diagnosed with a genetic cancer syndrome. However, 11% of survivors described a family history pattern which met Chompret criteria for screening for TP53 mutations associated with LFS. Our data suggests that familial cancer predispositions may be initially overlooked. Aperiodic and accurate ascertainment of family cancer history of childhood cancer patients and survivors is therefore recommended.

BACKGROUND: Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk.METHODS: Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2.RESULTS: A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk.CONCLUSION: We found that CDX2 downregulation is associated with MMR deficiency, right-sided tumors, and poor differentiation at both the mRNA and protein level. Whether CDX2 plays an active role in tumor progression in MSI/MMR-deficient tumors remains to be elucidated.

BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.

Multiple self-healing squamous epithelioma - Ferguson-Smith disease (MSSE) is an autosomal dominant inherited disease with multiple, recurrent, histologically malignant tumours that undergo spontaneous regression. The gene for MSSE has recently been identified as the transforming growth factor-beta receptor 1 (TGFBR1). Although rare, MSSE constitutes an important model of tumour-biology research. The discovery of the genetic background for MSSE paves the way for further elucidating the mechanisms involved in this peculiar self-healing cancer syndrome.

Multiple self-healing squamous epithelioma - Ferguson-Smith disease (MSSE) is an autosomal dominant inherited disease with multiple, recurrent, histologically malignant tumours that undergo spontaneous regression. The gene for MSSE has recently been identified as the transforming growth factor-beta receptor 1 (TGFBR1). Although rare, MSSE constitutes an important model of tumour-biology research. The discovery of the genetic background for MSSE paves the way for further elucidating the mechanisms involved in this peculiar self-healing cancer syndrome.

In recent years, the clinical validation of molecular targeted therapies inhibiting the action of pathogenic tyrosine kinase (TK) has been one of the most exciting developments in cancer research. In this context, medullary thyroid carcinoma (MTC) represents a promising model. It is well known that in MTC, the RET receptor TK and its signal transduction pathways, lead to subsequent neoplastic transformation. Several strategies aimed at blocking the activation and signaling of RET have been preclinically tested. The most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKI). However, although the inhibition of the RET pathway is actually one of the most studied for therapeutic purposes, other signal transduction pathways have been recognized to contribute to the growth and functional activity of MTC and are considered attractive therapeutic targets. To date, surgery represents the only curative treatment of MTC. Despite promising initial results, studies on targeted agents are in early stages and several issues regarding preclinical evaluations and clinical trials of new targeted agents in MTC are still unresolved. Now, available mouse models bearing mutations of RET or other genes, which spontaneously develop MTC, promise to improve preclinical evaluation of activity of targeted compounds. Furthermore, the rarity of the disease and the number of patients available for enrollment may lessen the relevance of clinical trials. A major effort needs to be made by endocrinologists and oncologists to refer their patients for multi-institutional trials in order to optimize them, perform translational studies and expedite the availability of novel beneficial selective therapies.

Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by the presence of at least one sebaceous gland tumour and a minimum of one visceral malignant tumour. Recently, microsatellite instability (MSI) has been detected in the tumours of patients with MTS and germline mutations of the hMSH2 and hMLH1 mismatch repair genes have been detected in some patients with this syndrome. To determine if the tumours of patients with MTS have widespread genomic instability and whether loss of heterozygosity (LOH) in the chromosomal regions containing hMSH2 and hMLH1 is detectable, MSI and LOH were examined at 10 dinucleotide repeats on chromosomes 2p, 3p, 5q, 9p, 17p and 18q. Data were obtained from six sebaceous gland tumours and two adenocarcinomas of the colon from three patients of two Muir-Torre families. MSI was detected at more than half of the loci tested in all sebaceous tumours examined. In addition, there was LOH at D2S119 in one sebaceoma and one sebaceous carcinoma from one patient. The colon carcinomas from two patients showed MSI at five of the 10 loci analysed. These results show that widespread MSI is a feature of tumours in patients with MTS. In addition, the finding of LOH at D2S119, a marker located in the vicinity of hMSH2, in sebaceous tumours of one patient indicates that this gene may have a pathogenetic role in this patient.