Damage Repair Defects Research Articles

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

TPS191 Background: Recent updates to genetic testing recommendations and approved treatment options for prostate cancer (PCa) patients (pts) have clarified the need for comprehensive genetic registries. Germline DNA damage repair (DDR) defects are present in over 10% of pts who develop metastatic castration-resistant prostate cancer (mCRPC) while 5-10% of pts with localized PCa have germline pathogenic variants in DDR genes. NCCN guidelines have recently expanded to address genetic testing to include high risk localized, node positive and metastatic disease, in addition to family cancer history criteria. In May 2020, the FDA approved 2 PARP inhibitors for mCRPC treatment. Genetic registries can address the critical need to identify pts for recently approved targeted treatments, understand real-world effects of targeted therapies, and expand clinical trials examining less common mutations. PROMISE is a prospective genetic registry equipped to meet these needs. Methods: 5,000 PCa pts will be screened via the online study portal and at-home germline testing to identify and enroll 500 eligible pts with germline pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) in the genes of interest: ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, HOXB13, MRE11A, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, TP53 and XRCC2. Additional genes may be added as evidence emerges. Eligible pts must be assigned male at birth and have documented PCa through tissue biopsy, and/or PSA >100ng/dL, and/or radiographic evidence of disease. Pts with or without prior genetic testing, including those with known pathogenic variants, are encouraged to enroll. Exclusion criteria are: inability or unwillingness to provide information for eligibility and incomplete inclusion criteria. Following germline testing, all pts will be offered genetic counseling and periodic newsletters with updates on treatments and clinical trials. Every 6 months, eligible pts will complete a patient-reported outcome (PRO) survey (EORTC QLQ-C30) and updated medical records will be obtained for clinical data abstraction. Eligible pts will enter long-term follow-up. The primary endpoint is the creation of a prospective genetic registry of PCa pts. Additional endpoints include: frequency of pathogenic or likely pathogenic germline variants of interest, recruitment of a control group with a VUS in the genes of interest, association between disease characteristics and germline testing results, comparison of PROs between disease subpopulations, longitudinal outcomes, and overall survival. Study duration will be 20 years (active recruitment: 5 years, follow-up: 15 years). PROMISE is recruiting at 10 US sites and has 282 subjects enrolled in the screening phase to date. PROMISE is sponsored and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT04995198.

Abstract P2-06-04: Pathognomonic long molecule footprints of backup repair pathways in homologous recombination deficient cancers

Abstract Background: Cancer genomes provide a durable record of the genetic alterations that are acquired during normal cell development and carcinogenesis from DNA damage and DNA repair defects. As DNA repair-deficient tumors often become dependent on backup repair pathways, mutational signatures found in such tumors are thought to reflect the absence of a particular repair pathway as well as the activity of the backup repair mechanism responsible for maintaining genome integrity. While homologous recombination (HR) deficiency is primarily a disorder of double-strand break (DSB) repair, the mutation classes most specifically associated with HR-deficiency in cancer are paradoxically small variants, namely single nucleotide variants and short deletions. Mechanistic and cytogenetic studies, however, indicate that HR-deficiency should compromise structural genomic integrity and yield complex rearrangements. Here we elucidate complex structural variants that are specific for HR-deficient cancers and identify rearrangements that differentiate BRCA1 from BRCA2 loss and illuminate divergent backup DNA repair mechanisms. Methods: To investigate the role of complex SVs in HR-deficient cancers, we assembled a cohort of 2,367 WGS profiles from four tumor types (breast, ovarian, prostate, and pancreatic cancer) known to be associated with HR-deficiency. We identified 48 BRCA1-/- and 87 BRCA2-/- cases and called samples lacking (mono- or biallelic) mutations in BRCA1, BRCA2, or any other HR associated gene (e.g. PALB2, RAD51C) as wild-type. To validate observed structural variant patterns associated with homologous recombination deficiency from this larger dataset, a new cohort of 49 cases of invasive breast cancer with known BRCA1 (N = 29) or BRCA2 (N = 20) deficiency was collected as part of a prospective research study at Memorial Sloan Kettering Cancer Center and sequenced with 10X-linked read WGS in addition to standard Illumina short-read WGS. Results: Analysis of nearly 2,400 short-read whole genomes revealed distinct quasi-reciprocal structural variants (SVs) highly enriched in BRCA1-/- versus BRCA2-/- cancers. Applying high physical coverage (>150X) long molecule WGS to 49 tumor-normal pairs from breast cancer patients with inherited BRCA1 or BRCA2 loss-of-function mutations, we show that these SVs are associated with distinct cis or trans somatic allelic phases despite having nearly identical short read WGS footprints. Trans (crossover) outcomes were found to give rise to large-scale chromosomal variants that mediate the loss-of-heterozygosity patterns previously described as a cardinal feature of HR-deficient cancers. We find that these quasi-reciprocal SVs can be explained as distinct template switching outcomes from a shared intermediate arising after replication fork stalling in HR-deficient cancers. Furthermore, our WGS analyses reveal that BRCA2 genomes are highly enriched in deletions that harbor long (50-1000bp) tracts of inexact microhomology. These events, validated by long molecule WGS, indicate that single-stranded annealing serves as an active backup repair pathway in BRCA2-/- but not BRCA1-/- cancers. Conclusions: These results provide direct genomic evidence linking large-scale structural changes in HR-deficient tumors with specific backup repair pathways that suggest novel, therapeutically targetable dependencies. Our findings elucidate backup repair mechanisms responsible for generating structural variation in HR-deficient tumors, demonstrate the genotype-specific divergence of such compensatory DNA repair, and provide genomic features that improve the detection accuracy of HR-deficiency with utility for the optimal selection of treatment. Citation Format: Jeremy Setton, Kevin Hadi, Huasong Tian, Arnaud Da Cruz Paula, Joel Rosiene, Zi-Ning Choo, Julie Behr, Xiaotong Yao, Olivier Elemento, Britta Weigelt, Nadeem Riaz, Jorge S Reis-Filho, Marcin Imielinski, Simon N Powell. Pathognomonic long molecule footprints of backup repair pathways in homologous recombination deficient cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-06-04.

Nickel nanoparticle-induced cell transformation: involvement of DNA damage and DNA repair defect through HIF-1\u03b1/miR-210/Rad52 pathway

BackgroundNickel nanoparticles (Nano-Ni) are increasingly used in industry and biomedicine with the development of nanotechnology. However, the genotoxic and carcinogenic effects of Nano-Ni and the underlying mechanisms are still unclear.MethodsAt first, dose–response (0, 10, 20, and 30 μg/mL) and time-response (0, 3, 6, 12, and 24 h) studies were performed in immortalized normal human bronchial epithelial cells BEAS-2B to observe the effects of Nano-Ni on DNA damage response (DDR)-associated proteins and the HIF-1α/miR-210/Rad52 pathway by real-time PCR or Western blot. Then, a Hsp90 inhibitor (1 µM of 17-AAG, an indirect HIF-1α inhibitor), HIF-1α knock-out (KO) cells, and a miR-210 inhibitor (20 nM) were used to determine whether Nano-Ni-induced Rad52 down-regulation was through HIF-1α nuclear accumulation and miR-210 up-regulation. In the long-term experiments, cells were treated with 0.25 and 0.5 µg/mL of Nano-Ni for 21 cycles (~ 150 days), and the level of anchorage-independent growth was determined by plating the cells in soft agar. Transduction of lentiviral particles containing human Rad52 ORF into BEAS-2B cells was used to observe the role of Rad52 in Nano-Ni-induced cell transformation. Nano-Ni-induced DNA damage and dysregulation of HIF-1α/miR-210/Rad52 pathway were also investigated in vivo by intratracheal instillation of 50 µg per mouse of Nano-Ni. gpt delta transgenic mice were used to analyze mutant frequency and mutation spectrum in mouse lungs after Nano-Ni exposure.ResultsNano-Ni exposure caused DNA damage at both in vitro and in vivo settings, which was reflected by increased phosphorylation of DDR-associated proteins such as ATM at Ser1981, p53 at Ser15, and H2AX. Nano-Ni exposure also induced HIF-1α nuclear accumulation, miR-210 up-regulation, and down-regulation of homologous recombination repair (HRR) gene Rad52. Inhibition of or knocking-out HIF-1α or miR-210 ameliorated Nano-Ni-induced Rad52 down-regulation. Long-term low-dose Nano-Ni exposure led to cell malignant transformation, and augmentation of Rad52 expression significantly reduced Nano-Ni-induced cell transformation. In addition, increased immunostaining of cell proliferation markers, Ki-67 and PCNA, was observed in bronchiolar epithelial cells and hyperplastic pneumocytes in mouse lungs at day 7 and day 42 after Nano-Ni exposure. Finally, using gpt delta transgenic mice revealed that Nano-Ni exposure did not cause increased gpt mutant frequency and certain DNA mutations, such as base substitution and small base insertions/deletions, are not the main types of Nano-Ni-induced DNA damage.ConclusionsThis study unraveled the mechanisms underlying Nano-Ni-induced cell malignant transformation; the combined effects of Nano-Ni-induced DNA damage and DNA repair defects through HIF-1α/miR-210/Rad52 pathway likely contribute to Nano-Ni-induced genomic instability and ultimately cell transformation. Our findings will provide information to further elucidate the molecular mechanisms of Nano-Ni-induced genotoxicity and carcinogenicity.Graphical

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer.

Platinum‐based chemotherapy is not standard of care for unselected or genetically selected metastatic castration‐resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next‐generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate‐specific antigen (PSA) decline and objective radiographic response. In the wild‐type BRCA2 subgroup, 35% had a >50% PSA decline (P = .006) and 16% radiographic response (P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months (P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non‐AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly‐(ADP)‐ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross‐resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum‐based chemotherapy in preselected mCRPC patients.

Overall survival using radium-223 (Ra223) in metastatic castrate-resistant prostate cancer (mCRPC) patients with and without DNA damage repair (DDR) defects.

121 Background: Ra223 is a therapeutic option for mCRPC patients (pts) with symptomatic bone metastases. DDR-defective prostate cancers, specifically those with homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This study assessed presence or absence of DDR alterations in mCRPC pts treated with Ra223, investigating the effect on efficacy and overall survival (OS). Methods: All pts included were treated with Ra223 and had genomic results from a comprehensive next-generation sequencing panel of DDR genes that directly or indirectly led to HRD, from primary or metastatic tissue. Exclusion criteria were prior platinum-based chemotherapy or treatment with poly-ADP ribose polymerase inhibitors (PARPi). Pts were grouped by presence (DDR+) or absence (DDR-) of pathogenic somatic and/or germline aberrations in DDR genes. Primary endpoint was OS, and secondary endpoints were time to alkaline phosphatase (ALP) progression, time to next systemic therapy and biochemical responses; comparing DDR+ and DDR– groups. Results: 93 pts were included in this two-centre retrospective study. Median age was 68 years. 56% received prior chemotherapy. Baseline characteristics where comparable between DDR status subgroups. 28 (30%) pts had mutations in DDR genes, most frequently occurring in ATM (8.6%), BRCA2 (6.5%), and CDK12 (4.3%) genes. DDR+ pts showed prolonged OS (median 36.3 vs. 17.0 months; HR 2.29; 95% CI 1.21-4.32; P= 0.01). Median time to alkaline phosphatase progression was 6.9 months for DDR+ pts and 5.8 months for DDR- pts (HR 1.48; 95% CI 0.87-2.50; P =0.15), and median time to next systemic therapy was 8.9 months for DDR+ pts and 7.3 months for DDR- pts (HR 1.58; 95% CI 0.94-2.64; P =0.08). A higher proportion of DDR+ pts completed Ra223 therapy (79% vs 47%; P= 0.05). No differences in biochemical (prostate-specific antigen, ALP) responses were seen. Conclusions: Pts harboring deleterious DDR aberrations more commonly completed Ra223, and derived a greater OS benefit. These findings need prospective confirmation, but support combination of Ra223 with PARPi or ATR inhibitors in DDR-defective mCRPC pts.

Abstract B049: DNA damage echoes are key to prostate cancer susceptibility to supraphysiologic androgen levels

Abstract Purpose: Prostate cancer cells are dependent on AR for growth and survival, but recent reports have shown a paradoxical role of supraphysiologic androgen in growth inhibition, known as hormone interference. Androgen stimulation in AR-overexpressing prostate cancer cells leads to formation of double-strand breaks (DSBs). Here, we investigate the potential mechanism of high androgen induced DSBs and growth inhibition and its effect on survival following androgen stimulation in combination with DNA damage repair inhibitors or defects. Experimental Design: AR-dependent LNCaP, AR overexpressing LNCaP and PC3, AR-independent PC3, and APIPC were used for this study. High levels of androgen (R1881)/ DHT and olaparib-induced DNA damage were evaluated by gH2AX and 53BP1 foci formation after 6 or 24h. For cell death assays the drug was administered continuously for 3 days following the plating day. DNA PKcs activity was determined by Ser2056foci formation and dissociation from chromatin was measured by Thr2609 foci. AR activity or DNA binding was evaluated by Ser81 AR phosphorylation. An ex vivo PDX model (LuCaP 96CR) was utilized to mimic the BRCA2 defect condition. Results: We demonstrated that supraphysiologic androgen treatment on androgen-dependent and AR-overexpressing prostate cancer cell lines resulted in a dose-dependent induction of widespread DSBs, which was augmented after PARP inhibition (olaparib). AR expression correlated with persistent DNA damage as AR-independent cells lacked DSBs. High androgen treatment significantly induced caspase activity and reduced survival in AR-overexpressing cells. Hyperactivated DNA PKcs was retained on chromatin following high androgen exposure in these cells, leading to impaired dissociation of DNA PKcs from chromatin and inducing DNA damage. AR phosphorylation at Ser81 was also in concordance with hyperphosphorylated DNA PKcs, particularly in AR-overexpressing cells following high androgen and olaparib treatment. HR-deficient, BRCA2-null cells induced more DSBs after high androgen treatment with or without olaparib and were susceptible to DNA PKcs inhibition following androgen treatment. In contrast to this, AR-overexpressing cells did not exhibit any DNA damage following DNA PKcs inhibition after high androgen exposure. Ex vivo PDX models demonstrated a synergistic interaction between olaparib and high levels of androgen-induced DSB formation as well as hyperactive DNA PKcs. Conclusions: These results suggest a potential mechanism of supraphysiologic androgen stimulated AR-induced DNA damage and proliferation inhibition. AR binds to DNA PKcs following high androgen and until AR levels become saturated DNA PKcs and AR stay on the chromatin, which leads to inefficient DNA damage repair. HR-deficient cells were particularly susceptible to high androgen. Our data provide a mechanistic rationale for the response of AR upregulated cells as well as DNA repair deficient cells to supraphysiologic androgen therapy in combination with PARP inhibition. Citation Format: Payel Chatterjee, Jared M. Lucas, Michael D. Nyquist, Eva Corey, Peter S. Nelson. DNA damage echoes are key to prostate cancer susceptibility to supraphysiologic androgen levels [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B049.

Abstract 917: Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients

Abstract Endocrine therapy resistance results in the death of majority of women diagnosed with breast cancer in the USA every year. Although a few markers can predict endocrine treatment failure, comprehensive understanding of the underlying cause and early detection of resistant population remains biggest challenge in the field. Recently, deficient expression or mutation in MutL mismatch repair components was found to cause 20% of intrinsic resistance in primary ER+ HER2- breast cancers. The role of other DNA damage repair (DDR) defects in inducing endocrine resistance therefore requires exploration. To address this question, a systematic study of associations between DDR dysregulation at DNA and RNA level and response to endocrine therapy was conducted using aggregated data from patient tumors from several neoadjuvant aromatase inhibitor (NeoAI) clinical trials. METABRIC, TCGA and Loi et al. datasets were used as validation datasets. Statistically significant correlations between endocrine therapy resistance and mutations in two single strand break repair (SSBR) pathways, i.e. nucleotide excision repair (NER; p=0.04) and base excision repair (BER; p=0.03), and one double strand break repair (DSBR) pathway, i.e. non-homologous end joining (NHEJ; p=0.004) were identified. A second set of analyses identified loss of expression of three genes: CETN2 and ERCC1 from the NER pathway and NEIL2 from BER as specifically associating with poor outcome despite endocrine treatment, emphasizing potential connections between NER and BER defects and endocrine treatment response. The functional role of CETN2, NEIL2 and ERCC1 loss in inducing intrinsic endocrine therapy resistance was experimentally validated in two breast cancer cell lines, and in ER+ PDX models. Finally, a DDR signature score was devised from baseline expression levels of candidate genes and was able to predict endocrine treatment failure in &amp;gt;30% of patients.In conclusion, this study describes a screening strategy for identifying novel predictive markers of endocrine therapy resistance in primary patient tumors. Three DDR pathways, NER, BER and NHEJ, were identified in clinical data as associating with endocrine resistance and validated using experimental model systems. Results reveal an understudied but impactful role for DDR pathways that may explain up to half of all endocrine therapy failure and open new avenues for early screening, predictive diagnostics and personalized medicine. Citation Format: Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N. Bainbridge, Matthew J. Ellis, Svasti Haricharan. Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 917.

Cooperative effect of chidamide and chemotherapeutic drugs induce apoptosis by DNA damage accumulation and repair defects in acute myeloid leukemia stem and progenitor cells

BackgroundMany conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed.ResultsWe report that a low-dose chidamide, a novel orally active benzamide-type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34+CD38− KG1α cells, CD34+CD38− Kasumi cells, and primary refractory or relapsed AML CD34+ cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro. Mechanistically, these events were associated with DNA damage accumulation and repair defects. Co-treatment with chidamide and the DNA-damaging agent IDA gave rise to the production of γH2A.X and inhibited posttranslationally but not transcriptionally the repair gene of ATM, BRCA1, and checkpoint kinase 1 (CHK1) and 2 (CHK2) phosphorylation. Finally, the combination of chidamide and IDA initiated caspase-3 and PARP cleavage, but not caspase-8 and caspase-9, and ultimately induced CD34+CD38− KG1α cell apoptosis. Further analysis of AML patients’ clinical characteristics revealed that the ex vivo efficacy of chidamide in combination with IDA in primary CD34+ samples was significantly correlated to peripheral blood WBC counts at diagnosis, while LDH levels and karyotype status had no effect, indicating that the combination regimen of chidamide and IDA could rapidly diminish tumor burden in patients with R/R AML.ConclusionsThese findings provide preclinical evidence for low-dose chidamide in combination with chemotherapeutic agents in treating recurrent/resistant AML as an alternative salvage regimen, especially those possessing stem and progenitor cells.

Abstract 3754: Hippo pathway effector Yes-associated protein and cisplatin resistance in transitional cell carcinoma of the bladder

Abstract Background: Transitional cell carcinoma of the bladder (TCC) arises from the cells lining the bladder and accounts for 90% of bladder cancers. Current standard of care for muscle-invasive TCC is surgery with perioperative cisplatin-based chemotherapy regimens. Some tumors are quite sensitive to cisplatin but others either acquire resistance or are refractory. A reduced drug availability, an increased efficacy of the DNA damage repair machinery or defects in the apoptotic process are the main mechanisms involved in cisplatin resistance. The Hippo tumor suppressor pathway controls multiple cellular functions that are important for tumorigenesis and drug-resistance, including proliferation, apoptosis and oxidative stress regulation. Specifically, the overexpression of Yes-associated protein (YAP), one of the two repressed-targets of this pathway, prevents tumor necrosis factor-induced apoptosis in mouse liver and protects cancer cells from chemotherapy-induced apoptosis. Intriguingly, this transcriptional co-activator has been shown to be involved in bladder cancer progression and to be a biomarker for poor prognosis of patients with TCC. Furthermore, in ovarian cancer, YAP has been shown to confer resistance to cisplatin. Thus, we hypothesized that YAP may be involved in cisplatin resistance in bladder cancer and could predict drug response in TCC patients. Methods: Cisplatin activity and YAP protein expression and localization were analyzed in different in vitro and in vivo models of TCC: 1) Collection of bladder cancer cell lines, genetically manipulated by knocking-down or overexpressing YAP; 2) Cell line models of cisplatin resistance, obtained by long term continuous in vitro exposure to increasing drug concentrations; 3) Two TCC patient derived xenograft (PDX) models and derived primary cells (RP-B-01 and RP-B-02) with different intrinsic sensitivity to cisplatin. Furthermore, by continuous in vivo cisplatin treatment (2.5 to 5 mg/Kg, 1x/week, i.p.), we are currently establishing a cisplatin resistant RP-B-02 model. In vitro cisplatin effect was evaluated in apoptosis, proliferation and colony formation assays. Results: YAP expression and nuclear localization was inversely correlated with cisplatin sensitivity in TCC cell lines. Cisplatin-resistant TCC cell lines expressed higher YAP than parental counterparts. Cisplatin-induced apoptosis was significantly increased by YAP knockdown in T24 cell line. In vivo cisplatin treatment showed a greater anti-tumor effect in the low YAP-expressing RP-B-02 model as compared to the high YAP-expressing RP-B-01 tumors. Expression of YAP in human TCC specimens will be also presented. Summary: Overall, these data suggest that YAP has a role in bladder cancer response to cisplatin and highlights the potential therapeutic application of YAP as a biomarker of cisplatin sensitivity in TCC patients. Citation Format: Eric Stefano Ciamporcero, He Shen, Sreenivasulu Chintala, Swathi Ramakrishnan, Sheng Yu Ku, Kiersten M. Miles, Stefania Pizzimenti, Candace Johnson, Jianmin Zhang, Giuseppina Barrera, Roberto Pili. Hippo pathway effector Yes-associated protein and cisplatin resistance in transitional cell carcinoma of the bladder. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3754. doi:10.1158/1538-7445.AM2014-3754

A Case of Xeroderma Pigmentosum Associated with Squamous Cell Carcinoma

Xeroderma pigmentosum is a rare autosomal recessive disorder characterized by extreme photosensitivity and defect in repair of damage to DNA Lentigenes, freckles, telangiectasia and the hyperpigmented cutaneous macules in the sun-exposed area and early development of cutaneous malignancies are observed. In addition to cutaneous symptoms, ophthalmologic changes and neurologic abnormalities can be associated. We report a case of xeroderma pigmentosum associated with squamous cell carcinoma in a 4-year-old girl. This case is thought to be more earlier development of malignancies than ever reported.

Clinical, Genetic and DNA Repair Studies on a Consecutive Series of Patients with Xeroderma Pigmentosum

We report clinical, genetic and biochemical findings in 13 families with the photosensitive genodermatosis, xeroderma pigmentosum. All patients had a defect in repair of DNA damage provoked by ultraviolet radiation. Eleven patients and their three affected sibs were defective in the excision repair of UVR induced DNA lesions while the other two were defective in post-replication repair. One in the former group was diagnosed prior to the development of permanent skin abnormalities and preventive measures succeeded for almost five years in maintaining a normal appearing skin. In addition, two cases were diagnosed prenatally and aborted therapeutically. Some patients' parents showed slightly reduced repair of UVR induced DNA damage. In xeroderma pigmentosum (XP), the defect in the excision of DNA lesions appears to be due to homozygosity for one of at least seven different mutations and, accordingly, XP patients can be assigned to seven so-called complementation groups, A to G. Of these, groups A, C and D are the most common. Somatic cell fusion allowed three of the families reported here to be assigned to group A, four to group C and four to group D. Fibroblasts of patients from these three groups were shown to differ not only in the degree and kinetics of their residual DNA repair but also in the kinetics with which their defect is complemented by fusion with normal or XP cells of other groups. This confirms that mutations of different genes play a role in XP and provides a basis for understanding how such genes interact to secure repair of DNA lesions in normal cells. We discuss the phenotype of XP from different complementation groups in relation to the severe neurological abnormalities which may develop and must be considered in genetic counselling. We also discuss the biochemical anomalies of XP and the cellular effects of physical and chemical agents which damage DNA. In the practical management of XP, the importance of early differential diagnosis and prompt initiation of treatment is emphasized. Lastly we review the relationship between DNA repair and skin cancer in XP.