The current results, based on a large cohort of Holocaust survivors who were exposed to a variety of severe deprivations, add to the conflicting and sparse knowledge on this issue and support the notion that this group has a small but consistent increase in cancer development. Cancer 2017;123:3335‐45 . © 2017 American Cancer Society .

Cancer was diagnosed in 22.2% of those who were granted compensation versus 16% of those who were denied compensation ( P < .0001). Adjusting for birth cohort, sex, country of origin, and period of immigration, both analyses revealed significant increased risks of developing cancer in those who were exposed. For those who were granted versus denied compensation, the hazard ratios were 1.06 ( P < .001) for all sites, 1.12 ( P = .07) for colorectal cancer, and 1.37 ( P = .008) for lung cancer. For those born in occupied countries versus nonoccupied countries, the hazard ratios were 1.08 ( P < .001), 1.08 ( P = .003), and 1.12 ( P = .02), respectively.

The study population included 152,622 survivors. The main analysis was based on a comparison between individuals who were entitled to compensation for suffering persecution during the war and individuals who were denied such compensation. A complementary analysis compared survivors who were born in countries governed by Nazi Germany with survivors born in nonoccupied countries. A Cox proportional hazards model was used, with the time at risk of cancer development starting on either January 1, 1960, or the date of immigration to the date of cancer diagnosis or death or the date of last follow‐up (December 31, 2006).

Holocaust survivors during World War II were exposed to various factors that are associated with cancer risk. The objective of this study was to determine whether Holocaust survivors had an increased risk for developing cancer.

INTRODUCTION According to estimates of the International Commission on Holocaust Era Insurance Claims, of the 688,000 Jews who survived World War II (WWII) and remained alive in 2003, about 40% were living in Israel1; the estimated numbers alive in Israel in 2003 and 2015 were 265,000 and 189,000, respectively.2, 3 The survivors who, during the war, were in countries occupied by Nazi Germany or its allies, were subjected to prolonged severe and intensive stressors, including metabolic insults (ie, starvation to the extent of restriction to 220‐800 Kcal/day with protein and micronutrient deficiencies), physical and chemical factors (eg, cold, overcrowding, exposure to known carcinogens), biologic agents (eg, infectious diseases), intense and strenuous physical activity, physical and emotional abuse, and psychological responses to stressors (eg, anxiety and sleep deprivation).4-6 Although all individuals surviving the war experienced some of the above‐mentioned stressors, it might be expected that the degree and mixture of exposures varied between individuals depending on their specific situation (being in a ghetto, a concentration camp, or a work camp; in hiding; a victim of the Nazi persecution; or a partisan or other fighter). Some of the above‐mentioned environmental exposures and lifestyle habits are known to be associated with increased or decreased risk of cancer.7-9 The association between metabolic factors and cancer is well documented.7, 10 There is a positive association between body mass index and the development of both colorectal and prostate cancers and between postmenopausal overweight and breast cancer.7, 9, 11 Through the hormonal axis, starvation influences menarche and menopause as well as premenopausal and postmenopausal hormone levels and modifies the expression of oncogenes and tumor‐suppressor genes.12-15 Observational studies have demonstrated that prolonged starvation may cause amenorrhea and influence fertility.13 Late onset of menarche and early menopause are generally associated with lower rates of hormone‐related cancers, such as breast and ovarian cancers.7, 14 The Netherlands cohort study15 explored the short‐term and long‐term effects of moderate caloric restriction on colon cancer during the Hunger winter (1944‐1945), in WWII (1940‐1944) and in the Economic Depression (1932‐1940) periods. The researchers observed that exposure to moderate caloric restrictions during childhood and adolescence during the Hunger winter was inversely associated with colon cancer development. The authors suggested that hormonal decrease of estrogen and insulin‐like growth factor levels in early life periods might lead to persistent epigenetic changes that decreased the risk for later cancer development in adulthood. However, most studies dealing with caloric restriction have investigated moderate reductions (range, 10%‐30%) in calories with general adequate nutrition,16 whereas data are sparse on the impact of severe caloric restriction on cancer development in combination with multifaceted stress conditions like those experienced by the Holocaust survivors.6 Among epidemiological studies that have assessed the effect of starvation on cancer development, most have dealt with breast cancer, with conflicting results.10, 11 Similarly, studies on colorectal cancers have mostly demonstrated a protective effect.8, 17, 18 The role of social environmental stressors that produce psychological responses in cancer development has been evaluated in many studies, and some have suggested an association through hormonal or immunologic pathways.19, 20 Stress works through the sympathetic nervous system and hypothalamic‐pituitary‐adrenal axis activation, together with related hormones that have an impact on the tumor microenvironment. The mechanism might involve several pathways, eg, cytokines, growth factors, receptors, hormones, corticotrophin‐releasing factors, and adhesion molecules. The variables involved are so numerous that it is difficult to isolate the cause or sequence of this relationship.21, 22 Another postulated mechanism for the possible impact of psychological stress on cancer development is through epigenetic modifications. Some epigenetic association studies have linked DNA hypermethylation to certain chronic diseases, including cancer.23 Studies in humans have indicated that changes in DNA methylation can be long‐lasting consequences of stressor exposure.24 However, other researchers claim that psychological stress cannot be considered a direct cancer risk factor25-27 and thus posit that stress impacts the risk of cancer through secondary mechanisms. These may include behaviors such as smoking, insomnia, alcohol abuse, and poor hygienic conditions, which might interact with psychological responses to stressors.22 Tobacco smoke is the leading risk factor for lung cancer.28 Smoking and heavy alcohol consumption are known risk factors for many other cancer types, including, laryngeal, oral cavity, colorectal, and breast cancers.28, 29 The adoption of the latter 2 harmful life style habits is strongly and positively associated with the development of post‐traumatic stress disorder after extreme stress, such as living in a war zone or engaging in combat.30, 31 Crowded and poor sanitary conditions in the concentration camps and ghettos increased exposure to infectious diseases.32 Associations of exposures to hepatitis B and C, human papillomavirus, and Helicobacter pylori with liver, cervical, and stomach cancers, respectively, are well known.33, 34 Holocaust survivors were exposed to many of these factors simultaneously, but their joint effect on cancer risk is unknown. The number of studies that directly assessed the impact of the Holocaust experience on cancer risk is limited, and the results were inconclusive.35, 36 The objective of the current study was to assess cancer rates in a large cohort of Holocaust survivors based on the history of their war experience (which was used as a marker of exposure). In this analysis, the assignment of survivors to exposure groups and information on cancer development were based on individual data.

MATERIALS AND METHODS Despite the many discussions conducted during the years by various Israeli official organizations, no single, common definition for being a “Holocaust survivor” exists.37 For practical purposes, the determined definitions for compensation were in accordance with international agreements and judicial processes and mainly referred to criteria of disability (see below descriptions of 1st and 3rd study groups). In 1952, the “West German Federal Indemnification Law” (known as BEG) was enacted and, after the “Reparations Agreement” between West Germany and Israel in 1957, the first Israeli law, the “Victims of Nazi Persecution Act,” was established. Over the years, the laws were developed gradually to allow compensation according to different criteria. The study population of this historical prospective cohort included Holocaust survivors who applied for compensation according to this set of Israeli laws. Two analyses, main and complementary, were performed. For the main analysis, 4 study groups were defined according to inclusion criteria of the relevant laws. Group A Group A includes individuals who applied for and were granted compensation under the “Victims of Nazi Persecution Act” (1957). This group was limited to Israeli Jews who were stateless refugees under the direct occupation of the Nazi Germany, as opposed to the Axis countries (unless individuals could prove they were in a camp or were subjected to violence in the Nazi regime); immigrated to Israel up to 1953; applied for compensation up to 1969; were recognized as persecuted based on selected conditions (eg, being in a closed ghetto, a concentration camp, or escaping under a false identity); and were classified as suffering from at least 25% disability (n = 77,688 individuals). Since 2001, individuals who complied with these criteria but had not applied for compensation up to 1969 were also granted compensation (n = 4239 individuals). Group B Group B includes individuals who were in concentration camps or work camps for at least 6 months or who were in ghettoes or living under a false identity or hiding for at least 18 months. This group has been added under the framework of the Article 2 fund (established in 1992) and the “Holocaust Survivors' Benefits Act” (established in 2007). The entitlement for compensation was based on 4 criteria: 1) receiving income maintenance, 2) having been a persecuted individual, 3) having lived in a hostile country, and 4) having lived under specific personal circumstances during the war (eg, in a ghetto). It should be noted that assignment to this group entitled individuals to expanded benefits and that eligible individuals were entitled to move from group A to group B. Disabled War Veterans Disabled war veterans include individuals who, between 1939 and 1945, served as soldiers in the allied armies, partisans, or the Red Army and were classified by the Israeli authorities as having at least 10% health disability (physical or mental disabilities that resulted from an injury or disease that occurred or worsened during the war). Denied Compensation The denied compensation group includes individuals who applied as Holocaust victims under the above‐mentioned laws but were found ineligible for compensation. This group, although they were in some ways caught up in the war in Europe, did not meet the legal criteria required for compensation. Leading causes for denial of compensation included time of immigration or application for compensation, residency sequence, geographic locations, minimal disability, and minimal time of residence in a camp or of persecution. Those who were denied compensation could reapply according to updates of the laws or changes in individual circumstances. Periodically, re‐examination of applications was initiated by the authorities for added protection of survivors' rights. 38 Survivors born in Germany, Poland, Austria, France, Netherland, Belgium, Yugoslavia, Hungary, Czechoslovakia, Latvia, occupied territories of the former Soviet Union, Belarus, Lithuania, Ukraine, Greece and Tunis (classified as “occupied countries”); and Survivors born in Romania, Bulgaria, Moldova, unoccupied territories of the former Soviet Union, Turkey, Italy, and Libya (classified as “nonoccupied countries”). For the main analysis, the first 3 groups, defined as “granted compensation”, were compared with the fourth, defined as “denied compensation”. For the complementary analysis, the first 3 groups were reclassified by country of origin. This classification was based on a general historic definition according to the Nazi occupation, which was adopted by governmental committees and the Rehabilitation Office. Two subgroups were defined: Holocaust survivors born in Nazi Germany or in direct Nazi‐occupied countries that were included in the “final solution”, as defined in the Wannsee Conference (known as “first line”), and Holocaust survivors from nonoccupied countries of Axis powers, allied powers, and neutral countries (known as “second line”).In this complementary analysis, countries were classified as follows: The compensation files did not include details regarding the exposure types, the nature of suffering of the survivors, or the specific eligibility/ineligibility criteria. Therefore, the compensation group (main analysis) and the country of birth (complementary analysis) served as markers for exposure (“granted compensation” vs “denied compensation” or “occupied countries” vs “nonoccupied countries”, respectively). Data were abstracted from the Rehabilitation Office at the Ministry of Finance (since 2009, this office was renamed the Holocaust Survivors' Rights Authority and is referred to herein as the “Rights Authority”) and the Conference on Jewish Material Claims Against Germany (referred to herein as the “Claims Conference”). These sources include registries of the Holocaust survivors who applied for compensation. The files were linked with the Israeli Central Population Registry (operating since 1948) to retrieve vital status and to the National Cancer Registry to update cancer diagnoses. The cancer registry (with a coverage rate of 94.2% for malignant solid tumors and 84.6% for hematopoietic tumors39) was established in 1960 and is notified of all malignant tumors, as mandated by law. For each malignancy, topography and morphology (according to the International Classification of Diseases for Oncology, 3rd edition), and the date of tumor diagnosis were obtained. The study was approved by the Chaim Sheba Medical Center review board committee. Crude proportions of cancer were calculated as the number of cases divided by the number of individuals in the cohort. Data analysis was based on a Cox proportional‐hazards model. The outcome variable was the time from January 1, 1960 (year of initiation of the cancer registry) to the date of cancer diagnosis (with follow‐up to December 31, 2006). Death events before a cancer diagnosis were handled in the Cox regression as censoring events. Individuals who immigrated to Israel later than 1960 (and up to 2006) were included in the risk sets from their time of immigration. Because the average number of follow‐up years varied between the groups, person‐years (PYs) were presented by study groups. The following covariates were included in the Cox model: exposure group, sex, age (year of birth), continent of birth (Europe, Asia‐Africa, or other), and immigration period (grouped into 10‐year intervals of year of immigration) to control for selection bias that might be related to year of immigration to Israel. Adjusted cause‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. To test the proportional hazards assumption, we split the follow‐up period into 2 parts (1960‐1980 and 1981‐2006), ran the Cox regression for each period separately, and compared the derived HRs. An interaction term between sex and exposure group was included and was identified as statistically significant. Therefore, we present results stratified by sex as well as overall. Two‐sided statistical tests were performed at the 5% level.

RESULTS For the main analysis, the study included 152,622 individuals who contributed 5,665,009 PYs. Of these, 142,591 individuals (5,219,342 PYs) were granted compensation (81,927 from group A, 46,491 individuals from group B, and 14,173 from the disabled war veterans group) and 10,031 were denied compensation (445,667 PYs). The complementary analysis included 142,134 individuals (5,651,034 PYs), of which 57.1% contributed to the occupied countries group (Table 1). Table 1. Description of the Study Population and of Cancer Development by Study Group Main Analysis Complementary Analysisa Variable Total Group A Group B Disabled War Veterans Denied Compensation Governed by Nazi Germany Not Governed by Nazi Germany Total no. 152,622 81,927 46,491 14,173 10,031 91,926 50,208 Person years (1960‐2006) 5,665,009 3,546,146 1,471,522 201,674 445,667 3,225,651 2,425,383 Sex: Men, % 51.1 48.9 44 94.6 40.8 52.7 50.1 Age at end of FU, y Mean ± SD 76.1 ± 8.9 75.5 ± 9.0 76.4 ± 8.7 80.7 ± 7.0 72.8 ± 8.3 76.6 ± 8.8 75.7 ± 8.9 Range 18‐110 18‐107 21‐110 37‐110 19‐105 21‐110 18‐108 Age at start of FU, y Mean ± SD 33.4 ± 8.6 33.0 ± 8.6 33.1 ± 8.3 40.9 ± 5.7 28.4 ± 7.4 34.3 ± 8.6 32.9 ± 8.5 Range 5‐74 9‐74 5‐73 9‐74 6‐59 5‐74 10‐73 Period of immigration, % <1960 71.4 99.3 36.6 8.4 94 64.3 80.2 1960‐1969 6.7 0.6 19.3 3.1 3.3 4 12.4 1970‐2979 5.9 0.05 14.1 16.6 0.7 8.3 2.7 1980‐1989 1.7 0.02 4.3 4.4 0.2 1.7 2 ≥1990 14.2 0.05 25.7 67.5 1.8 21.7 2.8 Age group at immigration, % <40 y 74.3 97.3 49.3 7.4 96.7 65.7 85.7 40‐59 y 11.8 2.6 29.1 15.5 1.5 13.9 10 ≥60 y 13.9 0.1 21.6 77.1 1.8 20.4 4.3 Latency, y Mean ± SD 36.5 ± 13.4 42.5 ± 6.6 31.1 ± 14.6 14.1 ± 10.9 43.6 ± 6.8 33.4 ± 14.8 40.5 ± 9.5 Range 0‐46 0‐46 0‐46 0‐46 0‐46 0‐46 0‐46 Dead as of 2006, % 29.7 28.7 24.4 64.2 12.9 33.1 26.7 Occupied countries, % 61.7 57 68.5 94.6 22 NA NA Cancer‐all sites, no. (%) 33,342 (21.9) 18,346 (22.4) 9555 (20.6) 3783 (26. 7) 1618 (16.1) 20,881 (22.7) 10,753 (21.4) Age at cancer diagnosis, y Mean ± SD 71.1 ± 10.6 70.0 ± 10.9 71.4 ± 10.2 77.1 ± 7.1 67.1 ± 10.8 71.7 ± 10.3 70.4 ± 11.0 The disabled war veterans group included mostly men (95%), but only 41% to 53% of the other groups were men. The mean age at end of follow‐up ranged from 73 to 81 years. Although nearly all individuals (>95%) in group A and in the denied compensation group and most individuals (80%) from nonoccupied countries immigrated to Israel before 1960, 26%, 68%, and 22% of individuals in group B, the disabled war veterans group, and the occupied countries groups, respectively, immigrated after 1990. The mean period between the end of WWII and end of follow‐up ranged between 55 and 59 years, and the mean calculated latency period from the start of follow‐up was 36.5 ± 13.4 years. During 1960 through 2006, 33,342 cancer cases were diagnosed; breast, colon, and prostate cancers were the most commonly diagnosed, constituting almost 50% of all cases. The crude cancer proportion was 22% and was lower in the denied compensation group (16%) compared with each of the granted compensation groups (22%, 21%, and 27% for group A, group B, and the war veterans group, respectively) (Table 1). For most sites, the crude incidence rate was lower in the denied compensation group than in the granted compensation groups. Among the group of individuals born in the occupied countries, higher rates were observed for colorectal, stomach, lung and renal cancers and leukemia than in the group of individuals born in the nonoccupied countries (Supporting Table 1; see online supporting information). The adjusted risk for cancer was lower among women, younger individuals (expressed by later birth cohort), and Asian‐born/African‐born individuals (Table 2). Compared with the reference group that was denied compensation (main analysis), a significant increased risk for developing cancer was observed among the total granted compensation group (HR, 1.06), group A (HR, 1.10), and the disabled war veterans group (HR, 1.53). The occupied countries group (complementary analysis) had an 8% increased risk compared with the nonoccupied countries group (95% CI, 1.05‐1.10). A sensitivity analysis for all‐site cancers among the latter groups removing the “disabled war veterans” produced similar results (HR, 1.06; 95% CI, 1.03‐1.09; data not shown). Table 2. The Risk of Developing Cancer (All Sites) for the Total Population and Stratified by Sex: Cox Proportional‐Hazards Model (Multivariate Analysis) Total Men Women Variable HR 95% CI HR 95% CI HR 95% CI Main analysis Sex Men 1.00 NA NA Women 0.83 0.81‐0.84 Birth cohort <1910 1.00 1.00 1.00 1910‐1914 0.87 0.81‐0.94 0.84 0.77‐0.92 0.92 0.81‐1.05 1915‐1919 0.76 0.71‐0.82 0.70 0.65‐0.76 0.86 0.77‐0.98 1920‐1924 0.68 0.64‐0.73 0.62 0.57‐0.67 0.79 0.71‐0.89 1925‐1929 0.60 0.56‐0.64 0.55 0.51‐0.60 0.67 0.60‐0.76 1930‐1934 0.46 0.43‐0.50 0.40 0.37‐0.44 0.56 0.50‐0.63 1935‐1939 0.35 0.33‐0.38 0.28 0.26‐0.31 0.46 0.41‐0.52 1940‐1945 0.27 0.25‐0.29 0.18 0.16‐0.21 0.39 0.34‐0.45 >1945 0.16 0.07‐0.39 0.07 0.01‐0.48 0.27 0.10‐0.71 Country of origin Europe 1.00 1.00 1.00 Asia‐Africa 0.60 0.57‐0.63 0.67 0.62‐0.71 0.54 0.50‐0.58 America, Oceania, Israel 0.82 0.56‐1.20 1.13 0.72‐1.77 0.46 0.22‐0.97 Period of immigration <1960 1.00 1.00 1.00 1960‐1969 0.99 0.94‐1.04 0.89 0.83‐0.95 1.09 1.02‐1.17 1970‐1979 1.04 0.99‐1.10 1.01 0.94‐1.08 1.09 1.01‐1.18 1980‐1989 1.00 0.92‐1.09 0.88 0.79‐0.99 1.18 1.03‐1.34 ≥1990 1.06 1.01‐1.12 0.99 0.93‐1.05 1.14 1.06‐1.23 Study group Denied compensation (ref) 1.00 1.00 1.00 Granted compensation 1.06 1.05‐1.08 1.07 1.06‐1.09 1.02 1.00‐1.04 Group A 1.10 1.04‐1.16 1.15 1.06‐1.25 1.06 0.99‐1.13 Group B 1.01 0.95‐1.07 1.06 0.97‐1.16 0.96 0.89‐1.04 Disabled war veterans 1.53 1.42‐1.64 1.58 1.43‐1.75 1.52 1.28‐1.81 Complementary analysisa Study group Not governed by Nazi Germany (ref) 1.00 1.00 1.00 Governed by Nazi Germany 1.08 1.05‐1.10 1.10 1.06‐1.14 1.05 1.02‐1.09 An analysis stratified by sex indicated higher cause‐specific HRs among men. The HR for total granted compensation versus denied compensation was 1.07 (95% CI, 1.06‐1.09) for men and 1.02 (95% CI, 1.0‐1.04) for women. For those in occupied countries versus nonoccupied countries, the HRs were 1.10 (95% CI, 1.06‐1.14) and 1.05 (95% CI, 1.02‐1.09) for men and women, respectively. A separate analysis by 2 follow‐up periods (1960‐1980 and 1981‐2006) revealed no major deviation from the proportional hazards assumption for the main comparative groups over the total follow‐up period. For the total granted versus denied compensation groups, the HR was 1.09 (95% CI, 1.03‐1.15) for the first period and 1.05 (95% CI, 1.04‐1.07) for the second period, whereas the value for the full period from 1960 to 2006 was 1.06 (95% CI, 1.05‐1.08). Similar small differences between the HRs of the two periods compared to the full period were observed in the subgroups of those granted compensation and in the complementary analysis (data not shown). An analysis by tumor site revealed increased risks for colorectal cancer (HR, 1.12 [P = .07] for the total granted vs denied compensation groups and HR, 1.08 [P = .003] for the occupied countries vs nonoccupied countries groups) and lung cancer (HR, 1.37 [P = .008] for the total granted vs denied compensation groups and HR, 1.12 [P = .02] for the occupied countries vs nonoccupied countries groups) (Table 3). Increased risks of these cancers were also demonstrated in each granted compensation group (colorectal cancer: group A [HR, 1.12; 95% CI, 0.99‐1.27], group B [HR, 1.14; 95% CI, 1.0‐1.31], and disabled war veterans [HR, 1.43; 95% CI, 1.21‐1.68]; lung cancer: group A [HR, 1.42; 95% CI, 1.13‐1.79], group B [HR, 1.21; 95% CI, 0.95‐1.57], and disabled war veterans [HR, 2.59, 95% CI, 1.94‐3.45]). These increased risks were statistically significant in men. For women, all these HRs were above 1.00 but reached statistical significance for lung cancer in group A and disabled war veterans (data not shown). According to Table 3, no risk was demonstrated for female breast and genital organs cancers neither for the total granted compensation versus denied compensation groups nor for the occupied countries versus nonoccupied countries groups. Table 3. The Risk of Developing Cancer by Disease Site for Granted Versus Denied Compensation and Countries Governed by Nazi Germany Versus Countries Not Governed by Nazi Germany (Cox Proportional Hazard Model) Main Analysis: Granted vs Denied Compensation Complementary Analysis: Countries Governed vs Not Governed by Nazi Germanyb Disease site HR 95% CI P HR 95% CI P Breast 0.98 0.88‐1.11 .8 1.01 0.95‐1.08 .7 Colon‐rectum 1.12 0.99‐1.27 .07c 1.08 1.03‐1.15 .003c Men 1.25 1.03‐1.51 .02c 1.08 1.01‐1.16 .03c Women 1.03 0.87‐1.21 .7 1.10 1.01‐1.20 .03c Prostate 1.03 0.88‐1.20 .7 1.07 1.0‐1.15 .05c Lung 1.37 1.09‐1.72 .008c 1.12 1.02‐1.22 .02c Men 1.37 1.01‐1.86 .04c 1.13 1.01‐1.27 .04c Women 1.40 0.98‐1.98 .06c 1.08 0.92‐1.26 .3 Bladder 1.18 0.98‐1.42 .07c 0.99 0.92‐1.06 .12 Pancreas 1.00 0.71‐1.40 .9 1.07 0.92‐1.25 .4 Men 0.72 0.46‐1.14 .2 1.21 0.98‐1.49 .08c Women 1.37 0.82‐2.30 .2 0.91 0.75‐1.17 .5 Thyroid 0.76 0.55‐1.04 .08c 1.25 1.04‐1.52 .02c Kidney‐renal 1.07 0.82‐1.41 .6 1.15 1.02‐1.31 .03c Acute leukemia 1.01 0.50‐2.02 .9 1.25 0.92‐1.71 .2 Chronic leukemia 1.20 0.85‐1.71 .2 1.33 1.14‐1.56 .001c Liver 1.65 0.71‐3.84 .2 0.66 0.50‐0.88 .004c Cervix 1.02 0.57‐1.83 .9 0.67 0.48‐0.94 .02c Stomach 1.12 0.84‐1.50 .4 1.15 1.02‐1.30 .02c Men 0.95 0.65‐1.39 .8 1.18 1.02‐1.37 .03c Women 1.39 0.88‐2.19 .16 1.10 0.89‐1.36 .4 Female breast and genital organsd 0.99 0.89‐1.09 .8 1.0 0.95‐1.06 .9 In the complementary analysis, significant HRs were also demonstrated for cancers of the prostate, pancreas (among men), thyroid, kidney, liver, cervix, and stomach (among men) and chronic leukemia in the occupied countries group compared with the nonoccupied countries group. Although the mean age at cancer diagnosis was oldest among the disabled war veterans group (77.1 years; probably reflecting their older mean age), the median age at diagnosis was similar between the other groups (Table 1).

DISCUSSION In the current study, we observed an overall cancer crude proportion of 22% and an HR of 1.06 for developing cancer when comparing the granted versus denied compensation groups and an HR of 1.08 among the occupied countries group compared with the nonoccupied countries group. Our results suggest an excess risk of developing lung and colorectal cancers among those most exposed to and surviving Holocaust conditions. These results were significant and consistent in the 2 different comparisons. The all‐sites, cause‐specific HRs were higher in men than in women, the risk for colorectal cancer was higher in men, and the risk for lung cancer was similar for both sexes. Risks of breast cancer and gynecologic cancers were similar in the different exposure groups. Several studies have investigated health outcomes in Holocaust survivors and have mainly demonstrated an increased risk of developing psychological disturbance, including stress, depression, and sleep disorders.40-42 Pasternak and Brooks assessed long‐term effects of the Holocaust on female reproductive function among Hungarian Jewish women and demonstrated that amenorrhea occurred in 94.8% of women during encampment.13 A cross‐sectional study (n = 1086 individuals) indicated that being born during WWII remained an independent risk marker for hypertension (odds ratio [OR], 1.52; 95% CI, 1.17‐1.99), diabetes mellitus (OR, 1.60; 95% CI, 1.21‐2.13), vascular disease (OR, 1.99; 95% CI, 1.33‐2.99), and metabolic syndrome (OR, 2.14; 95% CI, 1.48‐3.47).43 However, data on cancer risk among Holocaust survivors are sparse and inconclusive.35, 36 Keinan‐Boker et al35 evaluated cancer risk among Jewish Holocaust survivors based on 315,544 European‐born individuals by comparing those who immigrated to Israel after 1945 (exposed) and before 1945 (nonexposed). Like us, those investigators reported a significantly increased risk among the exposed group to develop cancer (all sites), colorectal cancer, and lung cancer. However, they also reported an increased risk of breast cancer in women. Among the limitations of the latter study were its ecologic nature and doubts over the comparability of those who immigrated to Israel before and after the war. The individually defined exposure and outcome used in our study add to the robustness of the results. Long‐term health effects of severe hunger were observed among survivors of the 872 days siege in Leningrad. The effects included increased blood pressure, increased risks of ischemic heart disease and stroke (partly mediated by blood pressure) among men, and an increased risk of breast cancer mortality among women who experienced the siege around puberty.44, 45 Other studies assessing the possible association between hunger and breast cancer in Norway (1200 Kcal per day) and Guernsey produced conflicting results.46, 47 A study that assessed the risk of developing breast cancer among 7303 women who were hospitalized before age 40 years for anorexia nervosa identified a significantly reduced risk for this cancer (standardized incidence ratio, 0.47; 95% CI, 0.19‐0.97), which was most pronounced in nulliparous women (standardized incidence ratio, 0.2; 95% CI, 0.03‐0.87).48 In the current analysis, no excess risk for breast cancer was identified. Regarding these inconsistent results, it has been suggested that the European Jewish WWII survivors experienced different stresses than European non‐Jewish WWII survivors.35, 49 For example, the Norwegian study50 demonstrated a reduced risk for breast cancer with a shorter term (<1 year) and less severe exposure to energy restriction (approximately 50% reduction in calorie intake and stable diet quality) compared with the exposed Jewish cohort during WWII. In addition, the survivors of the Dutch famine17 of 1944 had higher breast cancer rates in the face of energy restriction, which was more severe than that in the Norwegian survivors but less severe than that observed in the Jewish holocaust survivors.35 Holocaust survivors were exposed to various factors that have been investigated in other situations, as mentioned above, and many of them have been causally related to severe morbidity and increased mortality. In 2010, Hursting also mentioned that other factors, especially when combined with other severe stressors, underlie the cancer risk observed in those studies.51 In accordance with this, we could not a priori hypothesize the direction of the associations; therefore, 2‐sided tests were performed. Our results on colon cancer agree with those reported by Keinan‐Boker and colleagues.35 However, the results from other studies on the risk of colon cancer are sparse and inconsistent. Among 3901 men and 1429 women who experienced the Leningrad siege, no increased mortality of colon cancer was observed (men: HR, 0.83; 95% CI, 0.51‐1.34; women: HR, 0.65; 95% CI, 0.27‐1.52, respectively).45 Lower colorectal cancer risks were reported among individuals who were born during WWII in Norway and Estonia, countries that suffered from varying nutritional deprivation.52 The Netherlands Cohort Study also identified a weak inverse relation between energy restriction early in life and subsequent colon carcinoma risk in men and women.53 Most studies have demonstrated a positive association between body mass index and colon cancer. However, other nutritional risk factors also may affect colorectal tumor development. For example, an association between deficiencies of vitamin D, minerals, calcium, and folic acid and colon cancer has been reported.54, 55 These deficiencies were prevalent in the ghettos and concentration camps.4, 5 The question of whether psychological response to stressors affects cancer development has been evaluated in many studies. A review assessing the results from 70 longitudinal, prospective studies concluded that there is no psychological stress for which an influence on cancer development has been convincingly demonstrated.56 Studies have demonstrated that factors like exposure to chronic stressors, depression, and social support have been linked to tumor biology, viral oncogenesis, and cell‐mediated immunity. These factors accelerate cell tumor growth and molecular processes that facilitate the promotion of malignancy and increase tumor cell survival; however, there is no conclusive evidence regarding the role of these processes in the initiation of cancer per se.22, 57 In a prospective study conducted in Denmark investigating whether the death of a child is related to cancer risk in bereaved parents, a slightly increased overall cancer risk among mothers was observed (relative risk, 1.18; 95% CI, 1.01‐1.37). This association was most prominent for smoking‐related malignancies (relative risk, 1.65; 95% CI, 1.05‐2.59), and no significantly increased risk was noted for alcohol‐related malignancies, virus/immune‐related malignancies, or hormone‐related malignancies, including breast cancer.58 These results indicate that the impact of emotional stress on cancer development might be indirect and influenced by lifestyle habits, such as smoking. This observation might explain the increased risk for lung cancer observed in our study, which is in line with the risk described by Koupil et al, who reported higher mortality from respiratory cancer among men who were exposed to the Leningrad siege (HR, 1.35; 95% CI, 1.02‐1.78).45 Our results demonstrated differences in the overall risk for cancer development between men and women. These differences might be driven by the null results seen for breast and gynecologic cancers in women. Note that breast cancer is the most common malignancy among women in Israel and that, altogether, these cancers constituted greater than 40% of the cancers among women in this cohort. The advantages of this study include a large sample size, a long follow‐up period, and individual data on classification of both exposure (based on 2 separate definitions of being exposed to Holocaust conditions) and cancer diagnoses. The main disadvantages are that the definition of exposure was drawn from files created for legal purposes or was based on country of origin, which could lead to misclassification of exposure; that the results apply only to survivors who immigrated to Israel and were alive at least until 1953; and that cancers that occurred before 1960 were not counted. We note that, in 1953, the Israeli government began taking national responsibility for the provision of compensation to Holocaust survivors who were citizens of Israel and who immigrated to Israel from that year onward, and that the Israeli National Cancer Registry was established in 1960. Because, as mentioned above, only approximately 40% of the Jews who survived WWII were living in Israel, a question regarding the generalization of results might arise. Unfortunately, one cannot account for a possible bias that could have occurred by limiting the analysis to this group. A specific limitation is that the timing of Holocaust compensation legislation may have created a bias in the exposure classification. This could explain the null results that were observed from the comparison of cancer risk between group B and the denied compensation group (HR, 1.01; 95% CI, 0.95‐1.07). Because this group was formed relatively late (in 2007‐2008), these individuals had to be alive to apply for this additional compensation, and it is possible that only healthier survivors applied for it, creating a survival bias in this group. Because no data were available on the degree of the various exposures, no dose‐response effect could be assessed. Nevertheless, in our approach, the entitlement of survivors to compensation was based on criteria like staying in a ghetto, being persecuted in a hostile country, or suffering from a certain level of disability, which served as markers for actually experiencing the Holocaust conditions. Although the main exposure definition is subject to some misclassification, we believe this approach is superior to definitions based only on time and place of birth, as is done in most published studies on this topic. Moreover, our complementary analysis of those who were granted compensation, hypothesizing that individuals born in countries directly governed by Nazi Germany experienced more severe conditions for longer duration than individuals born in other countries, supports and strengthens our main results. The high rates of late immigration in the disabled war veterans group and in group B (68% and 26%, respectively compared to 0.05% and 1.8% in group A and in the denied compensation group, respectively) probably represent immigration from the former USSR (who arrived in Israel only since 1990 and mainly after the dissolution of the Soviet Union in 1991), introducing a possible survival bias in these groups. Nevertheless, such bias could decrease the observed effect because of undercounting cancer. In addition, this group of soldiers might be different from the other groups of civilians who experienced the war. Nevertheless, the inclusion of this group was based on the Claims Conference distinction, which recognizes soldiers and partisans as 1 of the Holocaust survivors groups, because most of them (especially Jewish partisans) experienced persecution, hid under a false identity, and were incarcerated in camps. In view of these possible biases, in the complementary comparison, we added a sensitivity analysis excluding the disabled war veterans and observed a similar increased risk in the occupied countries group compared with the nonoccupied countries group. In contrast, the high rates of early immigration (≥95%) observed in group A and in the denied compensation group suggest that these groups are complete and do not include substantial survival bias. To take into consideration concerns relating to survival bias, all analyses were adjusted for the period of immigration. Additional reassurances about the data's validity are the observations that cancer risk was 17% lower among women, increased with age, and was 40% lower in African‐born and Asian‐born individuals, all of which agree with the age‐specific, sex‐specific, and origin‐specific cancer rates in Israel.59 To the best of our knowledge, this is the largest and most comprehensive observational study assessing cancer risk among Holocaust survivors based on individual data. In line with some other previous findings, the consistency of our results observed in both men and women and in the 2 different approaches supports the association between being a Holocaust survivor and an increased risk of developing colorectal and lung cancers. These results indicate that survivors of the Holocaust have a small but consistent increase in cancer risk. The findings emphasize the complexity of the etiology of cancer development and the difficulties in determining the role of individual risk factors in the face of simultaneous exposures.

FUNDING SUPPORT No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES Mrs. Hakak reports personal fees from the Special Committee nominated to assess the causal association between the period of persecution by the Nazis and cancer incidence, Israeli Government, during the conduct of the study.

AUTHOR CONTRIBUTIONS All authors made substantial contributions to conception or design, analysis, and interpretation of data; writing–first draft or writing–critical revisions; had final approval; and were accountable for all aspects of the work.

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