Hereditary Cancer Research Articles

Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients with Gastric Cancer Associated with Hereditary Breast and Ovarian Cancer

Helicobacter pylori, a gram-negative, flagellated, helical bacterium, is a common cause of chronic gastric infection worldwide. According to the World Health Organization, H. pylori infection, a specific carcinogenic factor, was the leading cause of gastric cancer (GC) in 2014 worldwide (80%). H. pylori infection causes GC in >98% of patients in East Asian countries, including Japan. However, only some types of GCs are associated with H. pylori infection. Previous clinical studies have revealed that the bacterium secretes cytotoxin-associated gene A antigen, which inhibits the nuclear translocation of the breast cancer susceptibility gene 1 and 2 (BRCA1/2), a factor involved in DNA damage repair. This indicated an association between hereditary breast and ovarian cancers (HBOCs) and the development of GC. However, the detailed mechanisms underlying the development of GC caused by H. pylori infection remain unclear. Using the information on hereditary cancers obtained based on cancer genomic medicine, this study revealed that the incidence of GC was high in families with HBOC, with a preponderance for men from families with HBOC. Furthermore, the use of poly-adenosine diphosphate-ribose polymerase inhibitors in patients with hereditary GC is considered safe and effective. This study provides substantial evidence for guiding the establishment of early treatment for patients with advanced-stage/metastatic GC who harbored BRCA1/2 mutations.

Cross-cultural adaptation and validation of a French version of the perceived personal control questionnaire as an outcome measure instrument for genetic counseling.

The perceived personal control (PPC) questionnaire serves as an instrument to assess the concept of PPC, which refers to a person's perception of their ability to achieve positive outcomes while avoiding the negative effects of a given situation. Developed and used as a patient-reported outcome measure (PROM) in genetic counseling, the PPC questionnaire has been translated and validated in several languages, but not in French. The aim of this study was to cross-culturally adapt and validate a French version of the PPC questionnaire to evaluate genetic counseling services for hereditary breast and ovarian cancer (HBOC). After the translation into French, cognitive interviews were conducted with nine participants who had attended genetic counseling for HBOC to examine the adequacy of this French version and to verify participants' understanding of the questionnaire items. Cognitive interview data suggested that slight modifications should be made to four of the nine items and that it would be beneficial to add a short introduction to ensure that participants' interpretation corresponded to the intended meaning. Psychometric validation was then conducted with 99 participants who had also attended genetic counseling for HBOC. Counselees completed the questionnaire before and after their genetic consultation. The acceptability of the questionnaire was demonstrated by the presence of few missing items. The original three-factor solution was not confirmed by our exploratory factor analysis, suggesting that the questionnaire should be used as a one-dimensional instrument. The internal consistency of the questionnaire was high, with Cronbach's alpha of 0.89 before genetic counseling and 0.88 after. The significant increase in PPC scores before and after genetic counseling supports the responsiveness of the questionnaire. Convergent validity was confirmed by positive association with counselees' satisfaction with genetic counseling. These properties suggest the French PPC questionnaire is a valuable instrument for use as a PROM in genetic counseling research.

How Psychophysical Stress Can Mediate the Effects of Anxiety and Depression on the Overall Quality of Life and Well-Being in Women Undergoing Hereditary Breast Cancer Screening

Background: Women undergoing genetic counseling for hereditary breast cancer often experience a high emotional burden. Distress and stress in the initial phases of genetic counseling can be significant predictors of long-term psychological health, influencing quality of life and well-being. Objectives: This study aimed to evaluate the mediating role of psychophysical stress in the relationship of anxiety and depression with quality of life and well-being in women undergoing genetic counseling for BRCA1/2 mutations. Methods: A sample of 193 women from two genetic counseling clinics was assessed using validated questionnaires measuring the psychological variables under study. Sociodemographic and clinical characteristics were also considered. Results: The results of path analyses indicated a mediating role of psychophysical stress on the relationship between emotional distress and mental quality of life and well-being: higher levels of anxiety and depression were associated with increased psychophysical stress, which, in turn, was linked to a reduced perceived mental quality of life and well-being. Depression was the only significant psychological predictor of physical quality of life. Conclusions: These findings indicate that addressing both anxiety and depression in genetic counseling is crucial for enhancing mental and overall well-being. Interventions should focus on stress management to improve the quality of life, emphasizing depression treatment to enhance physical health outcomes.

"Should I let them know I have this?": Multifaceted genetic discrimination and limited awareness of legal protections amongst individuals with hereditary cancer syndromes.

Hereditary cancer syndromes (HCS), such as Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch Syndrome (LS), represent approximately 10% of all cancers. Along with medical burdens associated with the genetic risk of developing cancer, many individuals face stigma and discrimination. Genetic discrimination refers to negative treatment, unfair profiling or harm based on genetic characteristics, manifesting as "felt" stigma (ostracization without discriminatory acts) or "enacted" stigma (experiencing discriminatory acts). This study aimed to describe concerns and experiences of genetic discrimination faced by individuals with HCS. Semi-structured qualitative interviews were conducted with individuals with molecularly-confirmed HCS residing in Ontario, British Columbia and Newfoundland & Labrador, Canada. Purposive sampling was applied to obtain a diverse sample across demographic characteristics. Study procedures were informed by interpretive description; data were thematically analyzed using constant comparison. 73 participants were interviewed (39 HBOC, 34 LS; 51 females, 21 males, 1 gender-diverse; aged 25-80). Participants described multifaceted forms of genetic discrimination across healthcare, insurance, employment, and family/social settings. Participants valued the Genetic Non-Discrimination Act's protective intent, but demonstrated limited knowledge of its existence and provisions. Limited knowledge, coupled with policy constraints in non-legislatable settings and third-party use of proxy genetic information, hindered participants' ability to whistleblow or seek recourse. Our results illuminate a disconnect between intended protective effects of genetic non-discrimination legislation and ongoing genetic discrimination faced by individuals with hereditary conditions. To better support these individuals, this study encourages public outreach and knowledge translation efforts to increase awareness of non-discrimination legal protections.

Cancer Prevalence across Vertebrates.

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

Establishment of a clinical cancer genetics program for breast cancer in a resource-limited country; challenges and opportunities

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2, may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains.

The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis

Retinoic-acid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor subfamily consisting of RORα, RORβ, and RORγ. By binding to the ROR response elements (ROREs) on target gene promoters, RORs regulate a wide variety of cellular processes, including autophagy, mitophagy, oxidative stress, and inflammation. The regulatory roles of RORs are observed in cardiac cells, hepatocytes, pulmonary epithelial cells, renal cells, immune cells, and cancer cells. A growing body of clinical and experimental evidence suggests that ROR expression levels are markedly reduced under different pathological and stress conditions, suggesting that RORs may play a critical role in the pathogenesis of a variety of disease states, including myocardial infarction, immune disorders, cancer, and metabolic syndrome. Reductions in RORs are also associated with inhibition of autophagy, increased reactive oxygen species (ROS), and increased cell death, underscoring the importance of RORs in the regulation of these processes. Herein, we highlight the relationship between RORs and homeostatic processes that influence cell viability. Understanding how these intricate processes are governed at the cellular level is of high scientific and clinical importance to develop new therapeutic strategies that modulate ROR expression and disease progression.

Effects of personal cancer history and genomic risk information on mothers' psychological adaptation to inherited breast/ovarian cancer syndrome.

This study aimed to understand long-term coping responses of mothers (N = 287) receiving genetic counseling and testing (GCT) for hereditary breast/ovarian cancer (HBOC) syndrome. Psychological characteristics, including cancer-specific distress (Impact of Events Scale-Revised, α = .85) and coping (Brief COPE, α = .93) were assessed via structured personal communication, along with epidemiologic items assessing personal and family history of cancer. Genetic risk was determined by BRCA1/2 carriage. A principal component analysis was conducted on the coping measure to reduce its summary score to active coping (α = .91) with nine approach-oriented strategies responsive to stress. A multivariable regression model examined the main and interacting effects of clinical and psychological characteristics on maternal coping. Personal cancer history (F = 4.99, df = 1, p = .026), BRCA test result (F = 22.20, df = 1, p < .001), and cancer-specific distress (F = 17.80, df = 1, p < .001) were associated with greater engagement in active coping strategies. When controlling for cancer-specific distress, the interaction between personal cancer history and genetic test results was significant, such that women previously unaffected by cancer who received positive BRCA results reported the greatest levels of active coping (F = 7.92, p < .001). These findings indicate that previous cancer history, genetic risk, and psychological distress independently and jointly impact how women adapt to the threat of cancer over time.

Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity and/or its physical trapping of PARP1 onto DNA that perturbs not only PARP1 function in DNA repair and DNA replication, but also obstructs compensating pathways. The combined disruption of PARP1 with either of the hereditary breast and ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results in synthetic lethality. This has driven the development of PARP inhibitors as therapies for BRCA-mutant cancers. In this review, we focus on recent findings that highlight loss of PARP1 catalytic activity, rather than PARPi-induced allosteric trapping, as central to PARPi efficacy in BRCA deficient cells. However, we also review findings that PARP-trapping is an effective strategy in other genetic deficiencies. Together, we conclude that the mechanism-of-action of PARP inhibitors is not unilateral; with loss of activity or enhanced trapping differentially killing depending on the genetic context. Therefore, effectively targeting cancer cells requires an intricate understanding of their key underlying vulnerabilities.

Phenotypic evaluation of deep learning models for classifying germline variant pathogenicity.

Deep learning models for predicting variant pathogenicity have not been thoroughly evaluated on real-world clinical phenotypes. Here, we apply state-of-the-art pathogenicity prediction models to hereditary breast cancer gene variants in UK Biobank participants. Model predictions for missense variants in BRCA1, BRCA2 and PALB2, but not ATM and CHEK2, were associated with breast cancer risk. However, deep learning models had limited clinical utility when specifically applied to variants of uncertain significance.

Abstract B058: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients

Abstract Lynch Syndrome (LS) is the most common hereditary cancer syndrome, caused by germline mutations in one of the four DNA mismatch repair (MMR) genes. LS patients have a high risk to develop microsatellite instable (MSI) colorectal cancers. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are very common and shared among different tumors. When indels occur in coding genes they give rise to frameshift peptides (FSPs) with a very high potential to act as safe and potent neoantigens for a vaccine. NOUS-209 is a genetic vaccine encoding 209 neoantigens, shared across sporadic and hereditary MSI tumors, developed for interception and treatment of MSI tumors. Phase 1b trial evaluating NOUS-209 monotherapy in healthy LS carriers showed the induction of a potent and broad immune response. Here, we characterize indels encoding FSPs in a cohort of 50 incident MSI CRC from LS patients detected during routine screening (38 primary tumors; 22 metachronous tumors) by whole Exomeseq NGS. Overall, primary and metachronous tumors have a similar number of indels in coding genes. The repertoire of detected indels is only partially shared (27%) between the two categories of tumors. The 209 indels selected for the NOUS-209 vaccine are instead highly shared (95%) between primary and metachronous tumors. Moreover, the analysis of 8 patients for which both the primary and the metachronous tumor were available confirmed the presence of the 209 mutations both in the first and the second tumor. Therefore, the NOUS 209 vaccine has the potential to prevent tumor occurrence both in previvors and survivors by inducing a broad T cell immune response against recurrent FSP. Citation Format: Lorenzo De Marco, Elisa Micarelli, Joni Panula, Anna Morena D'Alise, Guido Leoni, Kalle E. Hokkanen, Eija Hämäläinen, Jukka-Pekka Mecklin, Elisa Scarselli, Toni Seppälä. Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B058.

Communicatively constructing resilience: Exploring family resilience in the experience of hereditary cancer

AbstractObjectiveThe goal was to explore how families communicate to cope with hereditary cancer conditions and identify factors that may enhance resilience and recommended decision‐making.BackgroundFamilies with Hereditary Breast and Ovarian Cancer syndrome (HBOC), Lynch syndrome (LS), and Li‐Fraumeni syndrome (LFS) have an increased lifetime risk of developing cancer. We use the communication theory of resilience (CTR) to examine how families engage in resilience and make health decisions about hereditary cancer risks over time.MethodWe conducted 42 dyadic interviews with families with HBOC, LS, and LFS. Themes emerged through qualitative analysis for each of the resilience processes outlined by CTR (crafting normalcy, communication networks, identity anchors, alternative logics, and foregrounding productive action while legitimizing negative feelings), illustrating how family members manage stressors associated with hereditary cancer over time.ResultsParticipants described enacting each of the five CTR processes to manage the acute and chronic stressors associated with hereditary cancer. We described themes that emerged within each of the five resilience processes.ConclusionFindings demonstrate the ways in which families managing hereditary cancer risks enact resilience processes and how these processes may have a complex relationship to coping and medical decision‐making.ImplicationsFindings demonstrate areas for intervention to support familial resilience.

Characteristics of Gut Microbiome in the Murine Model of Pancreatic Cancer with Damp-Heat Syndrome.

Murine models of pancreatic cancer with damp-heat syndrome were established based on two methods to explore the differences in the composition of intestinal flora and to seek characteristic genera with potential for model evaluation. In our study, thirty-four C57BL/6J male mice were randomly divided into a control group (Con), a model group (Mod), a classic damp-heat syndrome group (CDHS), and a climate-chamber group (CC). CDHS and CC groups were fed with a high-fat diet and glucose water, while the CDHS group was given 2.4 g/kg alcohol by gavage for 10 days, and the CC group was placed in a climatic chamber with a set temperature of (32 ± 1) °C and humidity of (92 ± 2)% for 10 days. The Mod group, CDHS group, and CC group underwent tumor-building experiments on day 11. Tumorigenicity was then assessed twice a week. After 4 weeks, feces, colon tissue, and tumor tissue were taken from the mice and were tested, and the mice were euthanized afterwards. Mice in the CDHS and CC groups showed symptoms similar to the clinical damp-heat syndrome observed in traditional Chinese medicine (TCM), and exhibited a worse general condition and more rapid tumor growth trend than those in the Mod group. The pathological examination indicated that inflammation was prevalent in the CDHS and CC groups. Both groups had a disrupted intestinal barrier and an overgrowth of pathogenic bacteria such as c_Gammaproteobacteria, o_Enterobacteriales, and g_Bacteroides. Their microbiota composition showed greater diversity. Intestinal flora may have a promising future in the discovery of indicators for evaluating a model of damp-heat syndrome in pancreatic cancer.

Reply to Importance of Identifying Physical Manifestations That Are Associated With Hereditary Cancer Predisposition: AXIN2 Mutation in an African-American Patient.

Reply to Importance of Identifying Physical Manifestations That Are Associated With Hereditary Cancer Predisposition: AXIN2 Mutation in an African-American Patient.

Next-generation sequencing (NGS) of anaplastic thyroid carcinoma identifies unreported mutations in 25 recurring genes

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare, aggressive form of thyroid cancer. Our prior work identified 6 molecular clusters of ATC with a possible de novo group. Secondary analysis of NGS data from 713 ATC cases was undertaken to identify less frequent and unreported gene mutations. Methods/Case Report Deidentified NGS results of 713 ATC cases were obtained from Foundation Medicine (FoundationOne CDx). The results were analyzed for frequency of gene mutations. A search of the literature and genomic databases (TCGA, NCI Genomic Data Commons, and cBioPortal) was performed to determine gene association with thyroid cancers including ATC. Results (if a Case Study enter NA) There are 25 gene mutations present in 5 or more cases that have not previously been reported in ATC and one gene found, MTAP, which has been discussed in a limited number of cases. The gene mutations found are listed from highest to lowest frequency (14.77% to 0.69%) as follows: MTAP, LRP1B, ASXL1, NUP93, MUTYH, NOTCH3, RAD21, CRKL, PIK3R1, FANCA, STAG2, BRCA2, FGF4, FGF3, FGF19, FBXW7, BRCA1, BCORL1, QKI, VHL, PRKN, GATA6, NKX2_1, KDM5C, CCND3, and BAP1. There are also 99 other gene mutations with 4 or fewer cases (0.14% to 0.77%) that have not previously been associated with ATC. MTAP was previously reported to be lost by immunohistochemistry in 6/27 (22.2%) ATC cases; MTAP loss was also reported to indicate a potential CDKN2A abnormality. Our larger data set supports that MTAP is lost in ATC with 98.6% of MTAP- deleted ATC also harboring CDKN2A deletion and 92.3% showing CDKN2B deletion (p-values &amp;lt; 0.0001), supporting MTAP and CDKN2A/B are often deleted together. Other significant genes include the hereditary cancer genes MUTYH, FANCA (autosomal recessive), and BRCA1/2 (autosomal dominant) and genes associated with clonal hematopoiesis. ASXL1 and STAG2 have previously been unreported in ATC while others such as DNMT3A, TET2, and BCOR were also present in our dataset. Conclusion Our findings demonstrate 124 genes mutated in ATC that have not been previously reported. Besides the previously reported MTAP in 6 cases, genes associated with hereditary cancer and clonal hematopoiesis were identified. MTAP is located adjacent to CDKN2A/B and is often codeleted with MTAP at a much higher frequency than previously reported. Identifying associations with other diseases could improve surveillance and options for earlier therapy of ATC. Finally, these findings warrant further research to determine their role in the pathogenesis and treatment targets of ATC.

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.

Li-Fraumeni Syndrome in Breast Cancer: Development of Theranostic Probes on Variation of P53

Li-Fraumeni Syndrome (LFS) is a hereditary condition characterized by a high predisposition to various cancers due to mutations in the p53 protein. Effectively targeting and treating this syndrome requires early detection and personalized treatment according to one’s specific nucleotide sequence. With the use of various forms of theranostics, LFS can be treated, increasing life expectancy; however, there is no absolute cure that could immediately end this syndrome. This paper delves into three different theranostic approaches: Gendicine (rAd-p53), Phesgo, and gold nanoshell poly(D, L-lactic-co-glycolic acid) nanoparticles (PLGA NPs). While each approach has limitations, PLGA nanoparticles exhibit advantages that outweigh their drawbacks, making it an attractive solution. This proposal will describe improvements to PLGA nanoparticles, which are a promising area of research for the development of new LFS treatments.

Analysis of the correlation between defunctioning stoma and postoperative low anterior resection syndrome in rectal cancer: a prospective cohort study

BackgroundTo evaluate the effect of stoma-related factors (stoma or no stoma, stoma type, and stoma reversal time) on the occurrence of low anterior resection syndrome (LARS), a highly prevalent condition that can develop after anal sphincter-sparing surgery for rectal cancer and impair quality of life, which includes fecal incontinence, fecal urgency and frequent defecation.MethodsPatients who underwent radical rectal cancer surgery from July 2018 to July 2022 in a tertiary hospital were included. Baseline data, tumor condition, operation condition and postoperative recovery were obtained by clinical observation. Follow-up data were collected by telephone follow-up. The chi-square and Fisher exact tests were used to analyse differences, coefficient of contingency was used to determine correlations, and independent risk factors for the occurrence of LARS (Patients with a score of 21 or more points were defined as having LARS using the LARS score) were further determined by binary logistic regression.ResultsA total of 480 patients met the inclusion criteria, of which 267 used a defunctioning stoma and 213 did not use a defunctioning stoma. There was a positive correlation between defunctioning stoma (P < 0.001, P < 0.001, P < 0.05) and the occurrence of LARS at 3, 6, and 12 months postoperatively, and there was no significant correlation between the stoma type or stoma reversal time and the occurrence of LARS at 3, 6 and 12 months postoperatively (P > 0.05). In binary logistic regression analysis, high BMI (Exp(B) = 1.072, P = 0.039), tumor closer to dentate line (Exp(B) = 0.910, P = 0.016), and ultra-low anterior resection (Exp(B) = 2.264, P = 0.011) increased the possibility of LARS at 3 months postoperatively; high BMI, proximity of the tumor to the dentate line, and ultra-low anterior resection were not independent risk factors for LARS at 6 months postoperatively (P > 0.05). However, proximity of the tumor to the dentate line (Exp(B) = 0.880, P = 0.035) increased the likelihood of LARS at 12 months postoperatively, while high BMI and ultra-low anterior resection remained non-significant as independent risk factors for LARS at 12 months postoperatively (P > 0.05).ConclusionsDefunctioning stoma was not an independent risk factor for the occurrence of LARS, whereas high BMI, tumor closer to dentate line, and ultra-low anterior resection were independent risk factors for the occurrence of LARS.Trial registrationNot applicable.

Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the novel NAMPT Inhibitor OT-82.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted TCA cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted a high-throughput drug screen in HLRCC cell lines, which identified a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Human HLRCC tumors and HLRCC-derived cell lines exhibited elevated NAMPT expression compared to controls. FH-deficient HLRCC cells, but not FH-restored HLRCC or normal kidney cells, were sensitive to NAMPT inhibition. HLRCC cell line viability was significantly decreased in both 2D and 3D in vitro cultures in response to the clinically relevant NAMPT inhibitor OT-82. NAMPT inhibition in vitro significantly decreased the total amount of NAD+, NADH, NADP, NADPH, and PAR levels and the effects of NAMPT inhibition could be rescued by the downstream NAD precursor nicotinamide mononucleotide, confirming the on-target activity of OT-82. Moreover, NAMPT inhibition by OT-82 in two HLRCC xenograft models resulted in severely reduced tumor growth. OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated renal cell carcinoma.