Antwi, Samuel O

AbstractBackground: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects.Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in AAs versus NHWs, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced.Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9–36.7; P < 0.001) compared with NHW cases (0.4%).Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among AAs.Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1364–70. ©2018 AACR.

Abstract Many risk factors have been firmly established for pancreatic cancer (PC), but the molecular processes by which known risk factors influence susceptibility to PC are not clear. There has been a recent upsurge of interest in the role of telomere length (TL), the protective DNA sequence repeats at chromosome ends, in pancreatic carcinogenesis. Given this heightened interest, we performed an in-depth, focused, and up-to-date review of the epidemiological evidence linking leukocyte TL (LTL) with PC risk. We searched MEDLINE, Embase, and the Cochrane Library databases for all published studies on LTL and PC risk, up to May 2017. Five studies were identified for review: 4 nested case-control studies and 1 retrospective case-control study. Two studies found opposite associations between LTL and PC risk: 1 found a dose-response positive association and the other found a dose-response inverse association. Two studies also found a “U-shaped” association, whereas another reported a weak nonlinear relationship. We offer potential reasons for the conflicting findings including variation in study design, biospecimen characteristics, and differences in interlaboratory measurements of TL. Future studies should carefully control for risk factors of PC that are associated also with telomere attrition and investigate the role of genetic variation in TL maintenance.

Inflammation plays a central role in pancreatic cancer etiology and can be modulated by diet. We aimed to examine the association between the inflammatory potential of diet, assessed with the Dietary Inflammatory Index (DII®), and pancreatic cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial prospective cohort. Our study included 101,449 participants aged 52–78 years at baseline who completed both baseline questionnaire and a diet history questionnaire. Energy‐adjusted DII (E‐DII) scores were computed based on food and supplement intake. Cox proportional hazards models and time dependent Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with participants in the lowest E‐DII quintile (most anti‐inflammatory scores) as referent. After a median 8.5 years of follow‐up, 328 pancreatic cancer cases were identified. E‐DII scores were not associated with pancreatic cancer risk in the multivariable model (HRQ5vsQ1 = 0.94; 95% CI = 0.66–1.35; p‐trend = 0.43). Time significantly modified the association (p‐interaction = 0.01). During follow up <4 years, there was suggestive evidence of an inverse association between E‐DII and pancreatic cancer (HRQ5vsQ1 = 0.60; 95% CI = 0.35–1.02; p‐trend = 0.20) while there was a significant positive trend in the follow up ≥4 years (HRQ5vsQ1 = 1.31; 95% CI = 0.83–2.08; p‐trend = 0.03). Similar results were observed for E‐DII from food only. Our study does not support an association between inflammatory potential of diet and pancreatic cancer risk; however, heterogeneous results were obtained with different follow‐up times. These divergent associations may result from the influences of undetected disease in the short‐term.

Alcohol consumption has been associated inversely with renal cell carcinoma (RCC) risk; however, no study has examined effect modification by germline variation in alcohol‐metabolizing genes. We investigated whether the association between alcohol intake and RCC risk is modulated by germline variants in alcohol dehydrogenase genes in a large case–control study. Data from 652 RCC cases and 1,366 non‐cancer controls were analyzed. Alcohol intake was assessed using a standardized risk factor questionnaire. Three previously genotyped polymorphisms in ADH6 and ADH7 with the TaqMan assay were examined. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using logistic regression, adjusting for covariates. Compared to non‐drinkers, ever consumption of alcohol was associated with lower RCC risk (OR = 0.52, 95% CI = 0.42–0.65). Analysis with cubic spline regression curve showed a “J‐shaped” relationship between alcohol drinks/day and RCC risk, such that there was no added benefit against RCC for consumption of more than two drinks/day. We observed effect modification by variation in rs1154454 (ADH7) (pinteraction = 0.007); a per unit increase in alcohol drink/day was associated with 35% lower RCC risk among non‐minor allele carriers, a 27% lower risk among those who carry one copy of the minor allele, but no association was observed among those with two copies of the minor allele. These findings indicate that alcohol consumption is associated with lower RCC risk. Consuming more than two drinks a day does not confer additional protection against RCC. The association between alcohol intake and RCC risk appears to be modulated by inter‐individual germline variation in alcohol‐metabolizing genes.

Abstract Background: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare primary malignancy of the liver which is distinct from hepatocellular carcinoma (HCC) or cholangiocarcinoma. HCC-CCA is presumed to have a poor prognosis and is not recommended for transplantation. The clinical and radiological presentation of HCC-CCA overlaps with HCC; thus, patients with these cancers may be mis-diagnosed as HCC and undergo liver transplantation, with the precise diagnosis ultimately determined on explant pathology. Patients undergoing transplant for presumed HCC receive loco-regional therapy (LRT), such as transarterial chemoembolization and radiofrequency ablation pre-transplant. Our goals were to (1) evaluate pre-transplant response to LRT, as predictors of recurrence and survival after transplant in HCC-CCA, and to (2) compare outcomes of transplant with adjuvant LRT in HCC-CCA and HCC. Methods: A retrospective study of 57 patients with presumed HCC who underwent liver transplantation and had pre-transplant LRT was performed. The study included 19 HCC-CCA cases and 38 HCC cases diagnosed on explant pathology, and individually matched (1:2) on age, sex, and Milan criteria. Response to LRT was determined by MRI performed before and after LRT. The response evaluation criterion in solid tumors (RECIST) was used to categorize treatment responses as “responders” if a patient had a complete or partial response or “non-responders” if a patient had stable or progressive disease. Recurrence rates, recurrence-free survival (RFS), and overall survival (OS) following LRT and transplant were compared between groups using Fisher’s exact tests. Results: The overall 1- and 3-year survival rates were 84% and 74% for HCC-CCA, and 95% and 87% for HCC, respectively. RFS at 1 and 3 years was 79% and 74% for HCC-CCA, and 92% and 87% for HCC (p-values &gt;0.05). For HCC-CCA, one-year OS and RFS in LRT responders were 92% and 83%, whereas for LRT non-responders, OS and RFS were 71% each. In contrast, for HCC, one-year OS and RFS in LRT responders were both 97%, whereas among non-responders, they were 83% and 67%, respectively. At three years, OS and RFS in responders were 92% and 75% for HCC-CCA and 88% and 90% for HCC, respectively; whereas among non-responders, OS and RFS rates were 43% and 57% for HCC-CCA and 83% and 50% for HCC, respectively (all p-value &gt;0.05). Conclusions: Short-term, post-transplant survival was poorer for HCC-CCA than HCC. However, OS among LRT responders for both cancers was similar. Response to LRT predicts favorable RFS in both HCC-CCA and HCC. Among non-responders, recurrence rate and RFS at three years were dismal and similar for both HCC-CCA and HCC, although OS is much lower for HCC-CCA patients. Response to pre-transplant LRT can be used for identifying HCC-CCA patients at high risk of recurrence and poor survival after liver transplantation. Citation Format: Yacob Y. Habboush, Samuel O. Antwi, Lori Chase, Tushar C. Patel. Response to loco-regional therapy as predictors of outcomes after transplantation for mixed hepatocellular cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2017-LB-237

Abstract Background: There have been varying reports on risk of different cancers, other than pancreatic cancer (PC), among first-degree relatives (FDRs) of PC patients. Because the pattern and scope of aggregation of PC with other malignancies in families of PC patients are not entirely clear, we investigated risk of 15 common malignancies among FDRs of unselected PC probands. Methods: The study included 17,181 FDRs with more than 336,000 person-years at risk. The FDRs were identified through sequentially enrolled PC probands (n=2,305) in the Mayo Clinic prospective pancreatic cancer patient registry from 2000-2016. Data on family history of cancer were provided by the probands at the time of enrollment in structured risk factor questionnaires. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing cases of each cancer type observed among the FDRs with those expected using data from the Surveillance Epidemiology and End Results Program (SEER). Stratified analyses were performed among siblings of the probands based on whether the related proband tested positive for a mutation in ATM, BARD1, BRCA1, BRCA2, CDKN2A, CHEK2, MUTYH, NBN, PALB2, or PMS2; or tested negative for mutation in a total of 25 sequenced cancer susceptibility genes. Results: Compared to the SEER reference population, risk of PC was two-fold higher than expected among the FDRs (SIR=2.04, 95% CI: 1.78-2.31) and 12-fold higher than expected among FDRs with history of PC in at least two blood relatives (SIR=11.99, 95% CI: 10.48-13.64). Siblings of mutation-positive probands had higher risk of PC (SIR=13.57, 95% CI: 6.19-25.76) than siblings of mutation-negative probands (SIR=8.91, 95% CI=6.73-11.57). For other cancer types, primary liver cancer was elevated among female FDRs (SIR=2.10, 95% CI: 1.34-3.12), whereas breast (SIR=3.16, 95% CI: 1.63-5.52) and ovarian (SIR =6.61, 95% CI: 1.33-19.31) cancers were elevated only among siblings of the mutation-positive probands. There also were suggestions of lower than expected risk of other malignancies, such as bladder, colorectal and prostate cancers, among the FDRs as compared with the SEER population. Conclusions: These findings confirm familial aggregation of PC with breast and ovarian cancers, and further suggest a potential aggregation of PC and primary liver cancer among female FDRs of PC probands. The elevated risks of breast cancer and ovarian cancer among siblings of the mutation-positive probands suggests a strong influence of genetic susceptibility shared with the related proband, possibly due to an inherited mutation in BRCA1, BRCA2, or PALB2. These findings lend support to genetic counseling and targeted screening of certain cancers in high-risk families. Citation Format: Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, William R. Bamlet, McWilliams R. Robert, Ann L. Oberg, Gloria M. Petersen. Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4269. doi:10.1158/1538-7445.AM2017-4269