Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer ...(SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11-4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29-9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58-16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91-5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21-7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes.
This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.
Abstract
Purpose: The four-kallikrein (4K) panel, commercially available as the 4Kscore, has been demonstrated to improve prediction of aggressive prostate cancer (PCa) compared to prostate-specific ...antigen (PSA) alone or PSA in combination with free PSA. However, the development and testing of the 4K panel has been limited to studies conducted primarily in White men.
Methods: We prospectively evaluated the 4K panel in a nested case-control study among African American (AA), Latino (LA), Japanese (JA), Native Hawaiian (NH), and White (WH) men in the Multiethnic Cohort (MEC). Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 (hK2) were measured among 2,227 incident PCa cases and 2,189 controls. We used area under the curve (AUC) calculations to compare the discriminative ability of the 4K panel to PSA for overall PCa, Gleason-Grade Group (GGG) 2 or higher, aggressive PCa (Gleason>7, non-localized disease, or death from PCa), and death due to PCa within and across all racial/ethnic groups.
Results: The mean ages of the cases and controls at blood draw were 68 (range 47–86) and 69 (range 47–87), respectively, and for cases, samples were drawn an average of 4.9 years prior to their PCa diagnosis (range <1–18 years). For men with elevated PSA (≥2.0 ng/ml; 1,669 cases and 663 controls), the AUC for overall PCa was 0.76 (95% CI 0.74–0.78) for the 4K panel compared to 0.72 (95% CI 0.70–0.74) for free plus total PSA and 0.67 (95% CI 0.65–0.70) for total PSA alone. Discrimination was slightly enhanced for the 4K panel for GGG≥2 (1,067 cases; 0.78 for panel versus 0.74 for free plus total PSA and 0.68 for total PSA only) and aggressive PCa (542 cases; 0.79 for panel versus 0.74 for free plus total PSA and 0.68 for total PSA only). Improvement of the 4K panel over total PSA alone was observed in each racial/ethnic group for all four PCa outcomes, most notably for GGG≥2 (AA, 0.71 vs. 0.66; LA, 0.82 vs. 0.71; JA, 0.80 vs. 0.69; NH, 0.90 vs. 0.77; WH, 0.77 vs. 0.69) and aggressive PCa (AA, 0.72 vs. 0.67; LA, 0.81 vs. 0.70; JA, 0.81 vs. 0.69; NH, 0.91 vs. 0.73; WH, 0.77 vs. 0.67).
Conclusion: The superior predictive ability of the 4K panel over PSA for overall and aggressive PCa across multiethnic populations indicates the broad clinical applicability of the 4K panel.
This abstract is also being presented as Poster A068.
Citation Format: Burcu F. Darst, Peggy Wan, Alisha Chou, Emily Vertosick, David V. Conti, Lynne Wilkens, Loic Le Marchand, Andrew Vickers, Hans Lilja, Christopher A. Haiman. The four-kallikrein panel discriminates prostate cancer and aggressive disease in a multiethnic population abstract. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR01.
Abstract Background: A growing body of research has shown the benefits of a healthy diet on a variety of cancer outcomes. Evidence is inconsistent for prostate cancer and research in diverse ...populations is limited. Methods: In the Multiethnic Cohort Study (MEC), we conducted a prospective cohort analysis to investigate the association of four diet quality indices (DQIs; AHEI-2010, aMED, HEI-2015, DASH; a higher score indicates healthier diet), three plant-based diet indices (PDI, hPDI, uPDI), two inflammatory (DII, EDIP), and two insulinemic dietary indices (EDIH, EDIR) (a higher score indicates more pro-inflammatory or pro-insulinemic diet) with incidence of prostate cancer (PCa) in 79,930 men from five racial/ethnic groups (White, African American, Japanese American, Latino, and Native Hawaiian). All dietary scores were constructed from a baseline quantitative food frequency questionnaire. Outcomes examined included total PCa, high-grade PCa (Gleason score > 7), advanced PCa (regional or distant), aggressive PCa (high-grade or advanced), and lethal PCa (distant or death due to PCa). Hazard ratios (HR) and 95% confidence intervals (CI) per one standard deviation (SD) increase in the dietary score were estimated from Cox proportional hazards models, overall and by race/ethnicity. Associations were considered nominally significant at P < 0.05. Results: During a mean follow-up of 18.9 years, a total of 9,759 incident PCa cases were identified, including 2,503 high-grade, 1,706 advanced, 3,430 aggressive, and 1,426 lethal PCa cases. None of the dietary scores was significantly associated with total PCa. We found a significant association between DII and advanced PCa (HR=1.08, 95% CI=1.01-1.15) overall and the association appeared to be the strongest in African Americans (HR=1.17, 95% CI=1.00-1.36) and Native Hawaiians (HR=1.29, 95% CI=0.98-1.68). We also observed weak associations of the four DQIs with advanced PCa (HR of 0.95-0.96, P of 0.07-0.10) in the overall population, among which a higher DASH score was significantly associated with a 15% (95% CI = 0.75-0.96) lower risk of advanced PCa in African Americans. In addition, we observed that several inflammatory (EDIP) and insulinemic (EDIH, EDIR) dietary scores were associated with lower incidence of advanced, aggressive, or lethal PCa (HR=0.89-0.95, P of 0.03-0.05), which requires further investigation. Conclusions: Our findings suggest that diets with high proinflammatory potential may increase risk of advanced PCa while following a healthy dietary pattern may reduce the risk of advanced PCa. Further studies are needed to better understand the inconsistent results across studies on diet and PCa risk and whether our findings can be replicated in other populations. Citation Format: Wei Xiong, Song-Yi Park, Anqi Wang, Peggy Wan, Lynne R. Wilkens, Loïc Le Marchand, Christopher A. Haiman, Fei Chen. Dietary patterns and prostate cancer risk in the Multiethnic Cohort Study 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 2203.
Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We ...investigated whether the African ancestry–specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval CI = 2.13–7.22) and 33.41 (95% CI = 10.86–102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17–25%) for TA heterozygotes and 38% (95% CI = 13–65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants.
We found that rs72725854, an African ancestry–specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
The African ancestry–specific prostate cancer risk variant at 8q24, rs72725854, is enriched in men diagnosed at younger ages and men with a prostate cancer family history. Carriers of this risk allele would benefit from regular and earlier prostate cancer screening.
Among men of European ancestry, diabetics have a lower risk of prostate cancer than do nondiabetics. The biologic basis of this association is unknown. The authors have examined whether the ...association is robust across populations in a population-based prospective study. The analysis included 5,941 prostate cancer cases identified over a 12-year period (1993–2005) among 86,303 European-American, African-American, Latino, Japanese-American, and Native Hawaiian men from the Multiethnic Cohort. The association between diabetes and prostate-specific antigen (PSA) levels (n = 2,874) and PSA screening frequencies (n = 46,970) was also examined. Diabetics had significantly lower risk of prostate cancer than did nondiabetics (relative risk = 0.81, 95% confidence interval (CI): 0.74, 0.87; P < 0.001), with relative risks ranging from 0.65 (95% CI: 0.50, 0.84; P = 0.001) among European Americans to 0.89 (95% CI: 0.77, 1.03; P = 0.13) among African Americans. Mean PSA levels were significantly lower in diabetics than in nondiabetics (mean PSA levels, 1.07 and 1.28, respectively; P = 0.003) as were PSA screening frequencies (44.7% vs. 48.6%; P < 0.001); however, this difference could explain only a small portion (∼20%) of the inverse association between these diseases. Diabetes is a protective factor for prostate cancer across populations, suggesting shared risk factors that influence a common mechanism.
Men of African-ancestry have elevated prostate cancer (PCa) incidence and mortality compared to men of other racial groups. There is support for a genetic contribution to this disparity, with ...evidence of genetic heterogeneity in the underlying risk alleles between populations. Studies of PCa among African men may inform the contribution of genetic risk factors to the elevated disease burden in this population.
We conducted an association study of >100 previously reported PCa risk alleles among 571 incidence cases and 485 controls among Uganda men. Unconditional logistic regression was used to test genetic associations and a polygenic risk score (PRS) was derived to assess the cumulative effect of the known risk alleles in association with PCa risk. In an exploratory analysis, we also tested associations of 17 125 421 genotyped and imputed markers genome-wide in association with PCa risk.
Of the 111 known risk loci with a frequency >1%, 75 (68%) had effects that were directionally consistent with the initial discovery population,14 (13%) of which were nominally significantly associated with PCa risk at P < 0.05. Compared to men with average risk (25
-75
percentile in PRS distribution), Ugandan men in the top 10% of the PRS, constructed of alleles outside of 8q24, had a 2.9-fold (95%CI: 1.75, 4.97) risk of developing PCa; risk for the top 10% increased to 4.86 (95%CI: 2.70, 8.76) with the inclusion of risk alleles at 8q24. In genome-wide association testing, the strongest associations were noted with known risk alleles located in the 8q24 region, including rs72725854 (OR = 3.37, P = 2.14 × 10
) that is limited to populations of African ancestry (6% frequency).
The ∼100 known PCa risk variants were shown to effectively stratify PCa risk in Ugandan men, with 10% of men having a >4-fold increase in risk. The 8q24 risk region was also found to be a major contributor to PCa risk in Ugandan men, with the African ancestry-specific risk variant rs72725854 estimated to account for 12% of PCa in this population.
Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, ...and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio OR = 1.55, 95% confidence interval CI = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP ...markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.
Abstract
Background: Healthy lifestyles have been observed to reduce the risk of pancreatic cancer. However, it is unknown whether this protective impact varies among individuals with different ...levels of genetic susceptibility for pancreatic cancer. Methods: We investigated the association between healthy lifestyles, genetic risk, and pancreatic cancer incidence in 70,780 participants (32,783 males, 37,907 females) from the Multiethnic Cohort Study (MEC), a prospective cohort of White, African American, Native Hawaiian, Japanese American, and Latino men and women. We calculated a healthy lifestyle factor score (HLFS) based on smoking status, alcohol intake, body mass index and physical activity. We also estimated genetic risk using an established polygenic risk score (PRS) of 49 pancreatic cancer risk variants. Cox regression was used to assess the independent and joint associations of the HLFS (analyzed as quintiles) and PRS (analyzed as quintiles and high/low categories) with pancreatic cancer risk. Models were adjusted for age at blood draw, sex, race, family history of pancreatic cancer, and in the genetic analyses, the first ten principal components to account for population stratification. Results: The analytical cohort was comprised of 23,643 (33.4%) Japanese Americans, 16,816 (23.8%) Latinos, 14,305 (20.2%) Whites, 10,645 (15.0%) African Americans, and 5,371 (7.6%) Native Hawaiians. There were 721 incident cases of pancreatic cancer from an average follow-up period of 13.7 (SD 4.8) years. Higher levels of the PRS were associated with a 25-62% increase in pancreatic cancer risk, compared to the first PRS quintile. These elevated risks were borderline significant for quintile 2 (HR 1.25, 95% CI 0.97-1.61) and statistically significant for quintile 3 (HR 1.35, 95% CI 1.05-1.73), quintile 4 (HR 1.46, 95% CI 1.15-1.87), and quintile 5 (HR 1.62, 95% CI 1.27-2.06). For the HLFS, higher quintiles were associated with a 10-27% decreased risk of pancreatic cancer, compared to the lowest quintile, but this was only statistically significant for the highest quintile (HR 0.73, 95% CI 0.56-0.94). When evaluating the HLFS by levels of the PRS (low 0-50% vs. high 50-100%), the association between the highest HLFS quintile and pancreatic cancer was more pronounced among those in the high PRS group (HR 0.64, 95% CI 0.45-0.91), compared to those in the low PRS group (HR 0.80, 95% CI 0.55-1.18). However, this difference in effect by PRS levels was not statistically significant (p-interaction=0.43). Conclusions: Our study demonstrates that including information on healthy lifestyles and genetic risk may improve the risk stratification of pancreatic cancer for multiethnic populations. In addition, it is possible that healthy lifestyles could provide more benefit to individuals at higher genetic risk.
Citation Format: Brian Huang, Adelynn Paik, David Bogumil, Fei Chen, Peggy Wan, Lynne Wilkens, Loic Le Marchand, David Conti, Christopher Haiman, Veronica Wendy Setiawan. Impact of healthy lifestyles and polygenic risk scores on pancreatic cancer risk: The Multiethnic Cohort Study abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A015.
Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, ...and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.
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