Farris, Alton B

Abstract Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Significance Statement Targeting plasma cells to reduce the risk of antibody-mediated rejection and decreased allograft survival due to anti-HLA donor-specific antibodies has not been explored in transplantation. After sensitizing eight rhesus macaques with two sequential mismatched skin allografts, the authors desensitized four with daratumumab (anti-CD38 mAb) and plerixafor (anti-CXCR4) before transplant. Compared with controls, the daratumumab-treated animals had significantly reduced donor-specific antibody levels and prolonged renal graft survival; however, this reduction was not maintained. Two patients treated with daratumumab—one with therapy-resistant acute kidney antibody-mediated rejection and a highly sensitized heart transplant candidate—exhibited a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and heart graft access. These findings suggest daratumumab merits investigation as a potential therapeutic strategy, although further research is needed. Background Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. Methods To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell–mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. Conclusions Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

Abstract Background: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. Methods: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. Results: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2; HR, 1.10; 95% CI, 1.06–1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). Conclusions: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. Cancer Epidemiol Biomarkers Prev; 24(8); 1229–38. ©2015 AACR.

Abstract Background: Tumor features such as stage, grade, and microsatellite instability (MSI) status have relevance for colorectal cancer survival whereas the prognostic role of body mass index (BMI) is unclear. We assessed the association of BMI and adult weight gain on colorectal cancer survival, overall and by strata of sex and MSI. Methods: Participants were identified from a multi-center cohort that includes 6,763 colorectal cancer patients with invasive colorectal cancer who were enrolled into the Colon Cancer Family Registry from 1997 to 2008. Vital status was updated through direct contact with patients/next-of-kin and/or linkage with mortality records. BMI 2 years before diagnosis, BMI at age 20 years, and adult weight gain were derived from self-reports of height and weight (i.e., weight 2 years before diagnosis and weight at age 20 years). Tumor MSI status was available for 4,987 patients. Multivariable, two-sided hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models, controlling for age at diagnosis, TNM summary stage (i.e., I, II, III, IV or missing), smoking (current, former, never), and study center. Results: After a maximum of 13.7 years of follow-up from enrollment to end-of-study (median: 5.3 years), 2,335 patients had died. Higher BMI 2 years before cancer diagnosis (per 5-kg/m2) was associated with higher risk of all-cause mortality overall (HR, 1.10; 95% CI, 1.05 to 1.14), with similar associations when stratified by sex (men: HR, 1.07; 95% CI, 1.02 to 1.14; women: HR, 1.11: 95% CI, 1.05 to 1.17; p-interaction: 0.18) and MSI status (MS-stable/MSI-low: HR, 1.08; 95% CI, 1.03 to 1.14; MSI-high, HR: 1.19; 95% CI, 1.02 to 1.40; p-interaction: 0.88). In joint models, with MS-stable/MSI-low and normal BMI as the referent group, risk of death was lower for those with MSI-high and normal BMI (HR: 0.77; 95% CI: 0.59 to 1.00), higher for MS-stable/MSI-low and high (≥30) BMI (HR: 1.23; 95% CI: 1.07 to 1.42), and essentially the same for MSI-high and high BMI (HR: 0.97; 95% CI: 0.72 to 1.30). Similar patterns of association were observed for BMI at age 20 years and when the outcome was colorectal cancer-specific mortality, although not all associations remained statistically significant for some of the smaller sub-group analyses. After controlling for BMI at age 20 years, adult weight gain was only modestly associated with all-cause mortality (per 5 kg HR: 1.01; 95% CI: 1.00 to 1.02; p-trend: 0.07). Conclusion: High pre-diagnosis BMI was associated with increased mortality after colorectal cancer diagnosis; this association was consistent for men and women and by tumor MSI status. These results also suggest that obesity attenuates the survival advantage observed with MSI-high tumors. Citation Format: Peter T. Campbell, Christina Newton, Polly A. Newcomb, Dennis Ahnen, John Baron, Sean Cleary, Michelle Cotterchio, A. Brad Farris, Jane Figueiredo, Roger C. Green, Loic Le Marchand, John McLaughlin, Amanda Phipps, John D. Potter, Andrew Renehan, Aung Ko Win, Noralane Lindor, Paul Limburg. Prospective study of body mass index and adult weight change with colorectal cancer survival, overall and by tumor microsatellite instability status. [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 LB-276. doi:10.1158/1538-7445.AM2014-LB-276

Abstract Background: To better understand colorectal cancer etiology and prognosis, archived surgical tissues were collected from Cancer Prevention Study II (CPS-II) Nutrition Cohort participants who were diagnosed with colorectal cancer. Herein, the methodology for this collection is described to help inform other efforts to collect tissues. Methods: The main components to accruing tissue were: (i) obtaining consent from participants or next-of-kin; (ii) contacting hospitals to request materials; and (iii) pathology review and laboratory processing. Results: In CPS-II, we identified 3,643 participants diagnosed with colorectal cancer between 1992/1993 and 2009. Of these, tissue could not be sought from cases verified through state cancer registry linkage (N = 1,622), because of insufficient information on tissue location. We sought tissue from the 2,021 cases verified using medical records, and received tissue from 882. When hospitals were contacted within 10 years of diagnosis, we received 87% of tissue materials; beyond that 10-year mark, we received 32%. Compared with the 2,761 colorectal cancer cases without tissue, the 882 cases with tissue were more likely to be alive, diagnosed more recently during follow-up, and had less-advanced staged disease. Cases with and without tissues were similar with respect to age at diagnosis, smoking, body mass index, physical activity, and other epidemiologic factors. Conclusions: Some of the most important elements in forming a tissue repository included having the cases' hospital contact and surgical accession information as well as contacting patients/next-of-kin and hospitals within 10 years of surgery. Impact: This tissue repository will serve as an important resource for colorectal cancer studies. See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.” Cancer Epidemiol Biomarkers Prev; 23(12); 2694–702. ©2014 AACR.