Defects In DNA Repair Genes Research Articles

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

Introduction: Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in pediatric acute-onset neuropsychiatric syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition. Methods: We analyzed genetic findings obtained from parents and carried out whole-exome sequencing on a total of 17 cases, which included 3 sibling pairs and a family with 4 affected children. Results: The DDR genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role. Conclusion: These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies.

Crosstalk between the DNA damage response and cellular senescence drives aging and age-related diseases.

Cellular senescence is a crucial process of irreversible cell-cycle arrest, in which cells remain alive, but permanently unable to proliferate in response to distinct types of stressors. Accumulating evidence suggests that DNA damage builds over time and triggers DNA damage response signaling, leading to cellular senescence. Cellular senescence serves as a platform for the perpetuation of inflammatory responses and is central to numerous age-related diseases. Defects in DNA repair genes or senescence can cause premature aging disease. Therapeutic approaches limiting DNA damage or senescence contribute to a rescued phenotype of longevity and neuroprotection, thus suggesting a mechanistic interaction between DNA damage and senescence. Here, we offer a unique perspective on the crosstalk between the DNA damage response pathway and senescence as well as their contribution to age-related diseases. We further summarize recent progress on the mechanisms and therapeutics of senescence, address existing challenges, and offering new insights and future directions in the senescence field.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers.

Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.

Early-Onset Merkel Cell Carcinoma is Associated with Germline Defects in DNA Repair Genes and a Rare Immunodeficiency

Background and aims: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer associated with immunosuppression and advanced age. Only 10% of patients present with MCC below age 50, and fewer than 0.1% present below age 30. Two patients with early-onset MCC (ages 14 and 22) were identified among patients followed at the NIH for X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease, which is caused by mutations in the magnesium transporter 1 (MAGT1) gene.

Dynamic Modelling of DNA Repair Pathway at the Molecular Level: A New Perspective.

DNA is the genetic repository for all living organisms, and it is subject to constant changes caused by chemical and physical factors. Any change, if not repaired, erodes the genetic information and causes mutations and diseases. To ensure overall survival, robust DNA repair mechanisms and damage-bypass mechanisms have evolved to ensure that the DNA is constantly protected against potentially deleterious damage while maintaining its integrity. Not surprisingly, defects in DNA repair genes affect metabolic processes, and this can be seen in some types of cancer, where DNA repair pathways are disrupted and deregulated, resulting in genome instability. Mathematically modelling the complex network of genes and processes that make up the DNA repair network will not only provide insight into how cells recognise and react to mutations, but it may also reveal whether or not genes involved in the repair process can be controlled. Due to the complexity of this network and the need for a mathematical model and software platform to simulate different investigation scenarios, there must be an automatic way to convert this network into a mathematical model. In this paper, we present a topological analysis of one of the networks in DNA repair, specifically homologous recombination repair (HR). We propose a method for the automatic construction of a system of rate equations to describe network dynamics and present results of a numerical simulation of the model and model sensitivity analysis to the parameters. In the past, dynamic modelling and sensitivity analysis have been used to study the evolution of tumours in response to drugs in cancer medicine. However, automatic generation of a mathematical model and the study of its sensitivity to parameter have not been applied to research on the DNA repair network so far. Therefore, we present this application as an approach for medical research against cancer, since it could give insight into a possible approach with which central nodes of the networks and repair genes could be identified and controlled with the ultimate goal of aiding cancer therapy to fight the onset of cancer and its progression.

MicroRNA-449a Inhibits Triple Negative Breast Cancer by Disturbing DNA Repair and Chromatid Separation.

Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3, BIRC5, BRCA2 and RAD51. The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC.

Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency.

Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. Study subjects were recruited at academic centers. Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. Rare deleterious variants in known and candidate genes associated with POI. Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

A decade of RAD51C and RAD51D germline variants in cancer

Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.

Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic.

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

The relationship between defects in DNA repair genes and autoinflammatory diseases.

Tissue inflammation and damage with the abnormal and overactivation of innate immune system results with the development of a hereditary disease group of autoinflammatory diseases. Multiple numbers of DNA damage develop with the continuous exposure to endogenous and exogenous genotoxic effects, and these damages are repaired through the DNA damage response governed by the genes involved in the DNA repair mechanisms, and proteins of these genes. Studies showed that DNA damage might trigger the innate immune response through nuclear DNA accumulation in the cytoplasm, and through chronic DNA damage response which signals itself and/or by micronucleus. The aim of the present review is to identify the effect of mutation that occurred in DNA repair genes on development of DNA damage response and autoinflammatory diseases.

Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data.

Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa.

An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer.

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.

Defects in DNA Repair Genes Confer Improved Long-term Survival after Cisplatin-based Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

Cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in muscle-invasive bladder cancer (MIBC). However, only a subset of patients (25–50%) have a pathologic complete response at cystectomy. Using a cohort of 58 patients from two phase 2 trials, our group previously reported that mutations in the ATM, RB1, and FANCC genes correlate with complete response to cisplatin-based NAC, and consequently improve OS and disease-specific survival (DSS). These trials enrolled patients with T2–4 (N0 or N1) MIBC and treated them with accelerated/dose-dense NAC with methotrexate, vinblastine, adriamycin, and cisplatin, or gemcitabine and cisplatin, with a plan for curative cystectomy. Updated long-term follow-up (median 74 mo) shows that significantly greater OS and DSS was maintained for patients with ATM, RB1, or FANCC mutations. The 5-yr survival rate for patients with at least one mutation was 85%, compared to 45% for patients without a mutation. On the basis of the associations with response and long-term OS and DSS, we propose that these alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients who are most likely to benefit from NAC before radical cystectomy. Patient summaryIn this report we looked at outcomes for patients with muscle-invasive bladder cancer treated with cisplatin-based chemotherapy before surgery (neoadjuvant) who had mutations in a set of DNA damage repair genes (ATM, RB1, FANCC) compared to those who did not. We found that patients who had at least one mutation in one of these genes survived longer after receiving cisplatin chemotherapy before surgery than patients who did not.

Evolving neoantigen profiles in colorectal cancers with DNA repair defects

BackgroundNeoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number of neoantigens is associated with patient response to immune therapies. The molecular processes governing the generation of neoantigens and their turnover in cancer cells are poorly understood. We exploited CRC as a model system to understand how alterations in DNA repair pathways modulate neoantigen profiles over time.MethodsWe performed whole exome sequencing (WES) and RNA sequencing (RNAseq) in CRC cell lines, in vitro and in vivo, and in CRC patient-derived xenografts (PDXs) to track longitudinally genomic profiles, clonal evolution, mutational signatures, and predicted neoantigens.ResultsThe majority of CRC models showed remarkably stable mutational and neoantigen profiles; however, those carrying defects in DNA repair genes continuously diversified. Rapidly evolving and evolutionary stable CRCs displayed characteristic genomic signatures and transcriptional profiles. Downregulation of molecules implicated in antigen presentation occurred selectively in highly mutated and rapidly evolving CRC.ConclusionsThese results indicate that CRCs carrying alterations in DNA repair pathways display dynamic neoantigen patterns that fluctuate over time. We define CRC subsets characterized by slow and fast evolvability and link this phenotype to downregulation of antigen-presenting cellular mechanisms. Longitudinal monitoring of the neoantigen landscape could be relevant in the context of precision medicine.

Defects in DNA repair genes and long-term survival in cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC).

4536 Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]

Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer.

Genomic studies of localized and metastatic prostate cancer have identified a high prevalence of clinically actionable alterations including mutations in DNA repair genes. In this manuscript, we review the current knowledge on DNA repair defects in prostate cancer and provide an overview of how these alterations can be targeted towards a personalized prostate cancer management. Twenty to 25% of metastatic prostate cancers harbor defects in DNA repair genes, most commonly in the homologous recombination genes. These defects confer increased sensitivity to platinum chemotherapy or poly (ADP-ribose) polymerase (PARP) inhibitors. Recent trials also support a synergistic effect of combining these therapies with androgen receptor-targeting agents. Identification of mismatch-repair defects could result in defining a prostate cancer population who may benefit from immune checkpoint inhibitors. These data have implications for family testing and early diagnosis, as many of these mutations are linked to inherited risk of prostate cancer. The DNA damage repair pathways are clinically relevant in prostate cancer, being a target for precision medicine; combination with standard-of-care androgen receptor (AR)-targeting agents may be synergistic.

Response to olaparib in metastatic castration-resistant prostate cancer with germline BRCA2 mutation: a case report

BackgroundProstate cancer is a heterogeneous disease, meaning patients would benefit from different treatment strategies based on their molecular stratification. In recent years, several genomic studies have identified prostate cancers with defects in DNA repair genes. It is known that the PARP inhibitor, olaparib, has a significant synthetic lethal effect on tumors with BRCA 1/2 mutations, particularly in ovarian and breast cancer.Case presentationIn this study, we describe a patient with metastatic castration-resistant prostate cancer (mCRPC) containing a BRCA2 germline mutation who underwent olaparib treatment. The efficacy of the treatment was monitored by serum TPSA level as well as mutation levels of circulating tumor DNA (ctDNA) using next-generation sequencing (NGS). The patient responded to the olaparib treatment as indicated by the minimal residual levels of TPSA and tumor-specific mutations of ctDNA in plasma after four months of treatment, although the patient eventually progressed at six-month post-treatment with significantly elevated and newly acquired somatic mutations in ctDNA.ConclusionsOur study provides evidence that mCRPC with BRCA2 germline mutations could response to PARP inhibitor, which improves patient’s outcome. We further demonstrated that NGS-based genetic testing on liquid biopsy can be used to dynamically monitor the efficacy of treatment.

The molecular limitations of biomarker research in bladder cancer.

Urothelial carcinoma of the bladder (UCB) is a common malignancy with limited systemic treatment options in advanced stages. Despite recent advances in immunotherapy, the majority of patients do not respond to these treatments. There is an unmet need for developing robust biomarkers to inform treatment decisions and identify patients who are likely to respond. A MEDLINE/PubMed literature search was performed, focusing on tissue-based and circulating biomarkers, and their potential in muscle-invasive UCB. UCB is a heterogeneous disease that consists of several clonal and subclonal populations, each with a mix of truncal and private genomic alterations. This inter- and intra-tumoral heterogeneous landscape results in the development of treatment resistance. Tumor heterogeneity also constitutes a barrier to the development of robust markers of response and resistance to chemotherapy and immunotherapy. Defects in DNA repair genes and a high tumor mutational burden independently confer sensitivity to cisplatin-based chemotherapy and checkpoint inhibitors. Oncogenic alterations such as FGFR3 mutations and fusions are associated with response to FGFR3 inhibitors. Several emerging potential biomarkers, including gene expression-based molecular subtypes, T-cell receptor clonality, and tissue- or blood-based immune-gene profiling, require prospective testing and validation. Tissue-based biomarkers such as PD-L1 immunohistochemistry have several limitations due to discordance in assay methodology and trial designs. Novel liquid-biopsy techniques are promising as potential biomarkers. Validated biomarkers that capture the complexity of the biology of both the tumor and the tumor microenvironment are needed in muscle-invasive UCB. Standardization of methods is critical to developing reliable biomarkers to guide clinical management.

Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility.

Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually frequent basal cell carcinoma (BCC) development, seen at Stanford Hospital and Clinics from January 2005 until December 2015, for germline analysis of 29 DNA repair genes. In parallel, a case-control retrospective review was performed to interrogate the association of malignancies with frequent BCC development in a large US medical insurance claims database (Truven), which included 13,264 individuals with 6 or more BCCs from 2007 to 2011. 19.7% of the frequent BCC cohort harbored pathogenic mutations in DNA repair genes: APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. Individuals with 6 or more BCCs had an increased risk of other malignancies, with a 3.5-fold increase in the frequent BCC cohort and a 3.2-fold increase in the Truven database. Individuals who developed frequent BCCs have an increased prevalence of germline mutations in DNA repair genes and increased malignancy risk. Our data implicate frequent BCC development as an external marker of inherited cancer risk.

Phenotypic characteristics of colorectal cancer in BRCA1/2 mutation carriers.

Mutations in the BRCA1/2 genes were recently shown to be associated with an increased risk for colorectal cancer. We characterized the largest cohort available of BRCA1/2 mutation carriers with colorectal cancer. We analyzed 32 patients with lower gastrointestinal cancers and germline BRCA1/2 mutations from two large academic hospital registries; 91% of patients were of Ashkenazi ancestry, 78% were women, and 62.5% were carriers of BRCA1 gene mutations. A high percentage of colorectal tumors (34.5%) had a mucinous histology and were located atypically in the left colon. Two patients had anal cancer with unusual histology and an additional patient had mucinous small bowel carcinoma. Gene expression analysis showed significant correlation between the gene signatures of left mucinous colorectal cancer and basal-like breast cancer. Our results imply that Ashkenazi BRCA1/2 mutation carriers with colorectal cancer might have unique characteristics with a high rate of left-sided, mucinous histology colorectal cancer, and possibly anal carcinoma. This report suggests a phenotypic influence of defects in DNA repair genes on colorectal tumors.