Hormone-related Cancers Research Articles

The association between non-HDL cholesterol and high-grade pancreatic neuroendocrine neoplasms.

High-density lipoprotein cholesterol (HDL-c) plays an important role in tumorigenesis in several endocrine-related cancers. Few studies have shown the effect of non-HDL-c in malignant tumors. The present study aimed to identify the association between non-HDL-c and high-grade pancreatic neuroendocrine neoplasms (PNENs). A total of 197 PNEN patients who underwent surgery were analyzed retrospectively. Clinical and histopathological features, such as patients' age and sex, tumor location and size, tumor grade, the level of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and fasting plasma-glucose levels were obtained. Non-HDL-c was calculated as total cholesterol - HDL-c. The relationships between those features and high-grade PNENs were identified using logistic regression analysis. Among the 197 patients with PNENs, a lower HDL-c level was more common seen in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.05). The non-HDL-c/HDL-c ratio was greater in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.01). Similarly, a greater proportion of patients with a non-HDL-c/HDL-c ratio larger than 5 was found in patients with poorly differentiated PNENs than in those with well-differentiation PNENs (P < 0.01). Multivariate logistic analysis showed that the non-HDL-c/HDL-c ratio was positively associated with poorly differentiated PNENs (odds ratio (OR) = 1.45, 95% conference interval (CI):1.13-1.87). Similarly, the risk of poorly differentiated PNENs increased significantly in patients with a non-HDL-c/HDL-c greater than 5 (OR = 14.13, 95%CI: 2.98-66.89). The risk of high-grade PNENs increased in patients with a high non-HDL-c/HDL-c ratio (OR = 1.27, 95% CI: 1.04-1.55), and the risk also increased markedly when the ratio was greater than 5 (OR = 5.00, 95%CI: 1.28-19.49). A high ratio of non-HDL-c/HDL-c was associated with high-grade PNENs or poorly differentiated PNENs.

Promoter mutation-independent TERT expression is related to the immune-enriched milieu in papillary thyroid cancer.

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors.

Incidence of prostate, colorectal and male breast cancers in relation with statins and testosterone replacement therapy: SEER-Medicare 2007–2015

IntroductionStatins and testosterone replacement therapy (TTh) have been inconsistently associated with a reduced risk of hormone-related cancers (HRCs, prostate [PCa], colorectal [CRC], and male breast cancers [BrCa]). Yet, the joint association of statins and TTh with the incidence of these cancers, and whether these associations vary by race, remains poorly understood. The objective of this retrospective cohort study is to examine the independent and joint effects of pre-diagnostic use of statins and TTh on the risk of HRCs, including PCa, CRC, and male BrCa. Materialsand Methods: In 105,690 men (≥65 yrs) identified using the SEER-Medicare 2007–2015 data, we identified 82,578 White and 10,256 Black men. Pre-diagnostic prescription of statins and TTh was ascertained for this analysis and categorized into four groups (Neither users, statins alone, TTh alone and Dual users). Multivariable Time-varying Cox proportional hazards and Accelerated Failure Time (AFT) models were performed. ResultsWe found inverse joint associations of statins and TTh with incident HRCs before (aHR: 0.39; 95 % CI: 0.35–0.44) and after 3 years of follow-up (aHR: 0.74; 95 % CI: 0.67–0.82). This included a lower risk for advanced stage HRC (only <3 years follow-up). Similar joint associations were identified with incident PCa, aggressive PCa, incident CRC, and its specific right- and left-sided CRC (only <3 years follow-up). In general, the inverse associations persisted among White (mainly <3 years follow-up) and Black men (high-grade HRC and <3 years follow-up). Findings from the AFT analysis were similar. DiscussionPre-diagnostic use of statins and TTh were, independently and jointly, associated with reduced risks of HRC and specific cancer sites at three years of follow-up overall, and among White and Black men. Greatest associations of HRCs risk reduction were observed among dual users (statins plus TTh). Further studies are needed to validate these findings, including larger samples of Black men, and male BrCa sites.

Dietary flavonoid intake and risk of hormone-related cancers: A population-based prospective cohort study

BackgroundDietary flavonoids may have potential effects on hormone-related cancers (HRCs) due to their anti-cancer properties via regulating hormones and suppressing inflammation and oxidative stress. We aimed to examine the association of flavonoid intake with risks of HRCs and whether this association was mediated by blood biomarkers involved in biological mechanisms. MethodsThis prospective cohort study from UK Biobank included 187,350 participants free of cancer when the last dietary recall was completed. The dietary intakes of flavonoids and subclasses were assessed using 24-hour dietary recalls. Venous blood was collected at baseline and assayed for biomarkers of inflammation, hormones, and oxidative stress. Hazard ratios (HR) and 95 % confidential intervals (CI) for the associations between flavonoid intake and HRCs risk were estimated by the cause-specific Cox proportional hazards model. The role of blood biomarkers in the flavonoids-HRCs association was investigated through mediation analysis. ResultsOver a median follow-up of 9.5 years, 3,392 female breast cancer, 417 ovarian cancer, 516 endometrial cancer, 4,305 prostate cancer, 45 testicular cancer, and 146 thyroid cancer cases were documented. Compared to the lowest quintile, multivariable-adjusted HRs (95 % CIs) in the highest quintile of total flavonoid intake were 0.89 (0.80–0.99) for breast cancer, 0.68 (0.50–0.92) for ovarian cancer, and 0.88 (0.80–0.98) for female-specific cancers. For subclasses, intakes of flavonols and anthocyanidins were inversely associated with the risk of female-specific cancers (Ptrend <0.05). Anthocyanidin intake was positively related to prostate cancer risk, whereas isoflavone intake was inversely linked to thyroid cancer risk (Ptrend <0.05). Additionally, certain biomarkers of inflammation, hormones and oxidative stress jointly mediated the association of flavonoid intake with the risk of female-specific cancers and prostate cancer. ConclusionsOur findings highlighted the importance of dietary flavonoids for the prevention of HRCs in the general population, providing epidemiological evidence for dietary guidelines.

Increased risk of subsequent primary lung cancer among female hormone-related cancer patients: A meta-analysis based on over four million cases.

The incidence rate of lung cancer in women has significantly increased over the past decade, and previous evidence has indicated a significant relationship between the elevated levels of sex hormones and the risk of lung cancer. Therefore, we hypothesized that female hormone-related cancer (FHRC) patients, including breast, endometrial, cervical, and ovarian cancer patients, may experience a higher risk of developing subsequent lung cancer. This meta-analysis aimed to identify the risk of lung cancer among FHRC patients compared to the general population. The PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI databases were searched up to May 11, 2022. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used to identify the risk of subsequent lung cancer after FHRC. Subgroup analyses based on the follow-up time and tumor type were also conducted. A total of 58 retrospective cohort studies involving 4,360,723 FHRC participants were included. The pooled results demonstrated that FHRC patients had a significantly increased risk of developing subsequent primary lung cancer (SIR=1.61, 95% CI: 1.48-1.76, P <0.001). Subgroup analysis revealed an obvious trend of increasing lung cancer risk over time (SIRs for <5years, ≥5years, ≥10years, ≥20years, and ≥30years after FHRC: 1.32, 1.59, 1.57, 1.68, and 1.95, respectively). In addition, subgroup analysis stratified by tumor type indicated an increased risk of developing subsequent lung cancer after breast (SIR=1.25, P <0.001), endometrial (SIR=1.40, P =0.019), cervical (SIR=2.56, P <0.001), and ovarian cancer (SIR=1.50, P =0.010). FHRC patients are more likely to develop lung cancer than the general population. Furthermore, the increased risk of subsequent primary lung cancer is more obvious with a longer survival time and is observed in all types of hormone-related cancer. International Platform of Registered Systematic Review and Meta-analysis Protocols: No. INPLASY202270044; https://inplasy.com/.

The Role of FOXA1 in Human Normal Development and Its Functions in Sex Hormone-Related Cancers.

Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the forkhead box (FOX) proteins, characterized by a conserved DNA-binding domain, play vital roles in various cellular processes, including cancer. The FOXA subfamily, encompassing FOXA1, FOXA2, and FOXA3, stands out for its pivotal role in mammalian development. FOXA1, initially identified in the liver, exhibits diverse expression across multiple organ tissues and plays a critical role in cell proliferation, differentiation, and tumor development. Its structural composition includes transactivation domains and a DNA-binding domain, facilitating its function as a pioneer factor, which is crucial for chromatin interaction and the recruitment of other transcriptional regulators. The involvement of FOXA1 in sex hormone-related tumors underscores its significance in cancer biology. This review provides an overview of multifaceted roles of FOXA1 in normal development and its implications in the pathogenesis of hormone-related cancers, particularly breast cancer and prostate cancer.

Fiber-type prebiotics and gynecological and breast cancers risk: the PrebiotiCa study.

Prebiotics may influence the risk of hormone-related female cancers by modulating the gut microbiota involved in estrogens metabolism. We evaluated the association of fiber-type prebiotic intake with breast, endometrial, and ovarian cancers. Data derived from a network of Italian hospital-based case-control studies (1991-2006), including 2560 cases of cancer of the breast (2588 controls), 454 of the endometrium (908 controls) and 1031 of the ovary (2411 controls). Inulin-type fructans (ITFs), and selected fructo-oligosaccharides (FOSs, nystose, kestose and 1F-β-fructofuranosylnystose) and galacto-oligosaccharides (GOSs, raffinose and stachyose) were quantified in food products. Prebiotic intake was estimated by multiplying food frequency questionnaire intake by the foods' prebiotic content. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were derived by multiple logistic regression models. Nystose intake was marginally directly associated with breast (OR for the 4th versus the 1st quartile 1.20, 95% CI: 1.00-1.45), ovarian (OR 1.39, 95% CI: 1.04-1.84) and endometrial cancer risk (OR 1.32, 95% CI: 0.85-2.03). High 1F-β-fructofuranosylnystose intake was inversely associated with ovarian cancer (OR 0.67, 95% CI: 0.52-0.85). ITFs, kestose, raffinose and stachyose were not associated with the three cancers. The intake of most fiber-type prebiotics was not appreciably and consistently associated with breast, endometrial and ovarian cancer risks.

Integrative bioinformatics approach yields a novel gene expression risk model for prognosis and progression prediction in prostate cancer.

Prostate cancer (PCa), a prevalent malignancy among elderly males, exhibits a notable rate of advancement, even when subjected to conventional androgen deprivation therapy or chemotherapy. An effective progression prediction model would prove invaluable in identifying patients with a higher progression risk. Using bioinformatics strategies, we integrated diverse data sets of PCa to construct a novel risk model predicated on gene expression and progression-free survival (PFS). The accuracy of the model was assessed through validation using an independent data set. Eight genes were discerned as independent prognostic factors and included in the prediction model. Patients assigned to the high-risk cohort demonstrated a diminished PFS, and the areas under the curve of our model in the validation set for 1-year, 3-year, and 5-year PFS were 0.9325, 0.9041 and 0.9070, respectively. Additionally, through the application of single-cell RNA sequencing to two castration-related prostate cancer (CRPC) samples and two hormone-related prostate cancer (HSPC) samples, we discovered that luminal cells within CRPC exhibited an elevated risk score. Subsequent molecular biology experiments corroborated our findings, illustrating heightened SYK expression levels within tumour tissues and its contribution to cancer cell migration. We found that the knockdown of SYK could inhibit migration in PCa cells. Our progression-related risk model demonstrated the potential prognostic value of SYK and indicated its potential as a target for future diagnosis and treatment strategies in PCa management.

Extra-nuclear and cytoplasmic steroid receptor signalling in hormone dependent cancers

Steroid hormone receptors are key mediators in the execution of hormone action through a combination of genomic and non-genomic action. Since their isolation and characterisation in the early 20th Century much of our understanding of the biological actions of steroid hormones are underpinned by their activated receptor activity. Over the past two decades there has been an acceleration of more omics-based research which has resulted in a major uptick in our comprehension of genomic steroid action. However, it is well understood that steroid hormones can induce very rapid signalling events in tandem with their genomic actions wherein they exert their influence through alterations in gene expression. Thus the totality of genomic and non-genomic steroid action occurs in a simultaneous and reciprocal manner and a greater appreciation of whole cell action is required to fully evaluate steroid hormone activity in vivo. In this mini-review we outline the most recent developments in non-genomic steroid action and cytoplasmic steroid hormone receptor biology in endocrine-related cancers with a focus on the 3-keto steroid receptors, in particular the androgen receptor.

Intimate Care Products and Incidence of Hormone-Related Cancers: A Quantitative Bias Analysis.

Intimate care products may contain substances associated with increased risk of hormone-related cancers. The relationship between genital talc use and ovarian cancer, in particular, has been well studied, but concerns about recall bias and exposure misclassification have precluded conclusions. We examined the association between intimate care products and female hormone-related cancers, accounting for potential biases, using data from a US-based cohort study. The Sister Study enrolled 50,884 women who had a sister with breast cancer. Data on genital talc use and douching were collected at enrollment (2003-2009) and follow-up (2017-2019). We used Cox proportional hazards models to estimate hazard ratios (HRs) for associations between intimate care product use and breast, ovarian, and uterine cancers. To account for potential exposure misclassification and recall bias, we conducted quantitative bias analyses under various exposure reassignment assumptions. Across considered scenarios, 41%-64% of participants douched and 35%-56% used genital talc. In models adjusted for exposure misclassification, genital talc use was positively associated with ovarian cancer (HR range, 1.17-3.34) Frequent douching and douching during young adulthood were positively associated with ovarian cancer, but neither douching nor talc was associated with breast or uterine cancer. Differential reporting of talc use by cases and noncases likely produces positive biases, but correcting for error still resulted in HRs above 1.0. For example, HR, 1.40 (95% CI, 1.04 to 1.89) when 25% of exposed cases and 10% of unexposed noncases had talc status reassigned. Although results show how differential recall would upwardly bias estimates, corrected results support a positive association between use of intimate care products, including genital talc, and ovarian cancer.

The Inflammasome molecular machinery as a novel source of diagnostic, prognostic, and therapeutic targets in endocrine-related cancers

The Inflammasome molecular machinery as a novel source of diagnostic, prognostic, and therapeutic targets in endocrine-related cancers

Abstract 3298: Unlocking the potential of OPM-383: A novel LRRK2 inhibitor in cancer therapy

Abstract Background: Leucine-rich repeat kinase 2 (LRRK2) plays a pivotal role in regulating various cellular processes, such as cell proliferation, survival, and inflammation. LRRK2 exhibits dual functionality as a serine-threonine kinase and as a GTPase. It is involved in the modulation of multiple signaling pathways, including WNT, MAPK, NF-kB and mTOR. Germline mutations in LRRK2 are associated with an increased risk of cancer, particularly hormone-related and colorectal cancers. LRRK2 also promotes tumor cell growth and survival in papillary renal and thyroid carcinomas, DLBCL and cholangiocarcinoma cells. OPM has designed and developed a novel oral LRRK2 inhibitor, OPM383, using its proprietary Nanocyclix® technology. In this study, we have evaluated the pharmacokinetic (PK) properties, efficacy and tolerability of OPM383 in a colon carcinoma model and a panel of patient-derived organoids. Materials and Methods: In vitro potency of our Type I inhibitor, OPM383, against full-length wild-type LRRK2 and the G2019S pathogenic LRRK2 mutant was assessed in in a Lanthascreen cell assay. For PK studies, we analyzed OPM383 plasma levels using UPLVC/MS-MS. Evaluation of inhibition of LRRK2 phosphorylation (Ser935) was assessed by western blot. MC-38 cells were inoculated into C57BL/6 mice. When tumor masses reached 75 mm³, mice were randomized to receive OPM383 (50 mg/kg, orally, daily), anti-PD1 antibody (10 mg/kg, ip, twice weekly), or their combination. OPM383 was also evaluated in patient-derived organoids using the SEngine-Paris® platform. Results: OPM-383 inhibited wild-type LRRK2 and LRRK2[G2019S] with an IC50 of 42 nM and 33 nM, respectively. OPM383 is highly selective among a panel of &amp;gt;400 protein kinases (only 6.7% cross-reactivity at 100 nM). The compound is permeable, metabolically stable and possesses drug-like properties. OPM-383 exhibited a favorable pharmacokinetic profile in mice (AUC of 11858 h*ng/mL and T max of 3 hours at a dose of 30 mg/kg via oral administration). Preliminary e-ADME results indicated moderate inhibition of CYP3A4BFC but no significant inhibition of CYPs 1A2, 2D6, 3A4BQ, 2C19, and 2C9 by OPM-383. After 90 minutes of oral administration in CD1 mice, we observed the inhibition of LRRK2 phosphorylation (Ser935) in the brain, kidney, and PBMCs. In assessing its potential antitumor effects, OPM383 was tested on a panel of patient-derived organoids. Notably, OPM383 inhibited the proliferation of 7 out of 29 patient-derived organoids after 6 days of exposure at various concentrations (&amp;lt;10 µM). In mice bearing subcutaneous MC38 tumors, OPM383 significantly inhibited tumor growth compared to the vehicle-treated group. Conclusion: This study characterizes a potent first-in-class LRRK2 inhibitor in cancer models. The findings suggest that OPM383 could serve as an attractive lead scaffold for designing and synthesizing a new class of kinase inhibitors for potential applications in cancer therapy. Citation Format: Maria Eugenia Riveiro, Petra Blom, Kenji Shoji, Jan Hoflack. Unlocking the potential of OPM-383: A novel LRRK2 inhibitor in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3298.

Evaluating the impact of pre-diagnostic use of statins and testosterone replacement therapy on mortality outcomes in older men with hormone-related cancers: Surveillance, Epidemiology, and End Results-Medicare 2007-2015.

The link between the pre-diagnostic use of statins and testosterone replacement therapy and their impact on hormone-related cancers, prostate cancer, colorectal cancer, and male breast cancer survival remains a topic of controversy. Further, there is a knowledge gap concerning the joint effects of statins and testosterone replacement therapy on hormone-related cancer survival outcomes. To examine the independent and joint effects of pre-diagnostic use of statins and testosterone replacement therapy on the risk of all-cause and cause-specific mortality among older men diagnosed with hormone-related cancers, including prostate cancer, colorectal cancer, and male breast cancer. In 41,707 men (≥65 years) of Surveillance, Epidemiology, and End Results-Medicare 2007-2015, we identified 31,097 prostate cancer, 10,315 colorectal cancer, and 295 male breast cancer cases. Pre-diagnostic prescription of statins and testosterone replacement therapy was ascertained and categorized into four groups (Neither users, statins alone, testosterone replacement therapy alone, and Dual users). Multivariable-adjusted Cox proportional hazards and competing-risks (Fine-Gray subdistribution hazard) models were conducted. No significant associations were found in Cox-proportional hazard models for hormone-related cancers. However, in the Fine-Gray competing risk models among high-grade hormone-related cancers, statins alone had an 11% reduced risk of hormone-related cancer-specific death (hazard ratio: 0.89; 95% confidence interval: 0.81-0.99; p 0.0451). In the prostate cancer cohort with both statistical models, the use of testosterone replacement therapy alone had a 24% lower risk of all-cause death (hazard ratio: 0.76; 95% confidence interval: 0.59-0.97; p 0.0325) and a 57% lower risk of prostate cancer-specific death (hazard ratio: 0.43; 95% confidence interval: 0.24-0.75; p 0.0029). Similar inverse associations were found among aggressive prostate cancer cases with testosterone replacement therapy alone and statins alone. No significant associations were found in the colorectal cancer and male breast cancer sub-groups. Pre-diagnostic use of statins and testosterone replacement therapy showed a survival benefit with reduced mortality in high-grade hormone-related cancer patients (only statins) and aggressive prostate cancer patients in both statistical models. Findings of testosterone replacement therapy use in aggressive prostate cancer settings could facilitate clinical trials. Further studies with extended follow-up periods are needed to substantiate these findings.

Association between brominated flame retardants and risk of endocrine-related cancer: A systematic review and meta-analysis

BackgroundThe incidence of endocrine-related cancer, which includes tumors in major endocrine glands such as the breast, thyroid, pituitary, and prostate, has been increasing year by year. Various studies have indicated that brominated flame retardants (BFRs) are neurotoxic, endocrine-toxic, reproductive-toxic, and even carcinogenic. However, the epidemiological relationship between BFR exposure and endocrine-related cancer risk remains unclear. MethodsWe searched the PubMed, Google Scholar, and Web of Science databases for articles evaluating the association between BFR exposure and endocrine-related cancer risk. The odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were used to assess the association. Statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. Begg’s test was performed to evaluate the publication bias. ResultsWe collected 15 studies, including 6 nested case-control and 9 case-control studies, with 3468 cases and 4187 controls. These studies assessed the risk of breast cancer, thyroid cancer, and endocrine-related cancers in relation to BFR levels. Our findings indicate a significant association between BFR exposure in adipose tissue and an increased risk of breast cancer. However, this association was not observed for thyroid cancer. Generally, BFR exposure appears to elevate the risk of endocrine-related cancers, with a notable increase in risk linked to higher levels of BDE-28, a specific polybrominated diphenyl ether congener. ConclusionsIn conclusion, although this meta-analysis has several limitations, our results suggest that BFR exposure is a significant risk factor for breast cancer, and low-brominated BDE-28 exposure could significantly increase the risk of endocrine-related cancers. Further research is essential to clarify the potential causal relationships between BFRs and endocrine-related cancers, and their carcinogenic mechanisms.

Legume intake and cancer risk in a network of case-control studies.

Evidence on the relationship between legume consumption and risk of specific cancer sites is inconclusive. We used data from a series of case-controls studies, conducted in Italy and in the Swiss Canton of Vaud between 1991 and 2009 to quantify the association between legume consumption and several cancer sites including oral cavity, esophagus, larynx, stomach, colorectum, breast, endometrium, ovary, prostate and kidney. Multiple logistic regression models controlled for sex, age, education, smoking, alcohol, body mass index, physical activity, comorbidities, and consumption of fruit, vegetables, processed meat and total calorie intake were used to estimate the odds ratios (OR) for different cancer sites and their corresponding 95% confidence intervals(CI). For female hormone-related cancers, the models also included adjustments for age at menarche, menopausal status and parity. Although most of the estimates were below unity, suggesting a protective effect, only colorectal cancer showed a significant association. Compared to no consumption, the OR for consuming at least one portion of legumes was 0.79 (95% CI: 0.68-0.91), the OR for consuming two or more portions was 0.68 (95% CI: 0.57-0.82) and the estimate for an increment of one portion per week was 0.87 (95% CI: 0.81-0.93). The inverse association between legume consumption and colorectal cancer suggests a possible role of legumes in preventing cancer risk.

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

BackgroundReports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.MethodsWe identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.ResultsGenome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.ConclusionsThis is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Function of Steroid Receptor Coactivators in T Cells and Cancers: Implications for Cancer Immunotherapy.

Steroid receptor coactivator (SRC) family members (SRC1, SRC2 and SRC3) are transcriptional co-regulators. SRCs orchestrate gene transcription by inducing transactivation of nuclear receptors and other transcription factors. Overexpression of SRCs is widely implicated in a range of cancers, especially hormone-related cancers. As coactivators, SRCs regulate multiple metabolic pathways involved in tumor growth, invasion, metastasis, and chemo-resistance. Emerging evidence in recent years suggest that SRCs also regulate maturation, differentiation, and cytotoxicity of T cells by controlling metabolic activities. In this review, we summarize the current understanding of the function of SRCs in T cells as well as cancer cells. Importantly, the controversies of targeting SRCs for cancer immunotherapy as well as possible reconciliation strategies are also discussed.

Gender-affirming care and endocrine-related cancers.

With the increasing number of transgender and gender diverse (TGD) individuals who are seeking gender-affirming care, there is a clear need for the development and collection of evidence-based data to establish guidelines for patient care. TGD individuals are estimated to represent 0.3 to 4.5% of the world population. Gender-affirming care that includes hormone therapy helps to align the body of a transgender person with their gender identity. Hormone therapy requires monitoring for both safety and efficacy. The extent to which gender-affirming hormone therapy alters cancer risk remains unknown. Because of a lack of comprehensive data collection pertaining to this patient population, endocrine cancer data including incidence and outcomes is limited. Dedicated research is needed to help address the gap in knowledge pertaining to the risk of cancer in the TGD population.

Cumulative incidence of second primary cancers in a large nationwide cohort of Danish cancer survivors: a population-based retrospective cohort study

A new primary cancer is a serious late effect of a pre-existing cancer diagnosis, and can be attributed to hereditary cancer syndromes, immune or hormonal factors, cancer treatment, or modifiable lifestyle or environmental factors. We investigated the absolute and relative incidence of second primary cancers in a large cohort of Danish cancer survivors. Furthermore, we examined the association between alcohol-related, smoking-related, virus-related, and hormone-related first and second primary cancers. In this retrospective cohort study, we identified a cohort of Danish adults (aged ≥40 years) diagnosed with cancer from Jan 1, 1997, to Dec 31, 2014 and alive 1 year after diagnosis. Follow-up was from date of first cancer diagnosis and lasted up to 24 years, ending on Dec 31, 2020. Cohort identification and information on second primary cancers was obtained from the Danish Cancer Registry, and comorbidity and sociodemographic information was obtained from Danish population-based registries. Overall, and for 27 cancer types, cumulative incidence functions and Cox proportional hazard regression models were used to estimate the incidence of second primary cancer and death, and hazard ratios (HRs) and 95% CIs of second primary cancer adjusted for sex, age and year of diagnosis, cohabitation status, income, and comorbidity. 457 334 Danish adults were included in our study (230 150 [50·3%] male individuals and 227 184 [49·7%] female individuals; median age at diagnosis 68·3 years, IQR 59·7-76·6; median follow-up 3·6 years, IQR 0·6-9·3). The cumulative incidence of second primary cancer increased over time from 6·3% (95% CI 6·2-6·4) 5 years after diagnosis to 10·5% (10·4-10·6) 10 years after diagnosis and to 13·5% (13·4-13·7) 15 years after diagnosis. The highest cumulative incidence of second primary cancer 10 years after diagnosis was observed in survivors of cancers in the larynx (21·8%, 20·5-23·1), oropharynx and oral cavity (19·5%, 18·7-20·3), and bladder and urinary tract (18·5%, 18·0-19·0). Survivors of cancers related to alcohol (HR 1·09, 95% CI 1·06-1·13), smoking (1·73, 1·68-1·78), diet high in red or processed meat (1·32, 1·24-1·39), or virus (1·23, 1·13-1·35) were at increased risk of developing a second cancer with the same aetiology, whereas having had a hormone-related first cancer was associated with lower risk of a second hormone-related cancer (0·77, 0·73-0·81). Our results could help optimise prevention efforts targeting modifiable risk factors to reduce risk of developing a second primary cancer. Nordic Cancer Union and The Health Foundation (Helsefonden).

Targeted radionuclide therapy in endocrine-related cancers: advances in the last decade.

Targeted radionuclide therapy plays an increasingly important role in managing endocrine-related tumors and significantly advances the therapeutic landscape for patients with these diseases. With increasing FDA-approved therapies and advances in the field, come an increased knowledge of the potential for long-term toxicities associated with these therapies and the field must develop new strategies to increase potency and efficacy while individualizing the selection of patients to those most likely to respond to treatment. Novel agents and modalities of therapy are also being explored. This review will discuss the current landscape and describe the avenues for growth in the field currently being explored.