Increased cancer incidence in Holocaust survivors and the implications for survivors of other extreme events

KEYWORDS:

• Cancer
• Developmental origin of health and disease [DOHaD]
• epigenetics
• Holocaust survivors
• transgenerational effects

1. Introduction

Cancer is a multifactorial disease caused by multiple etiological factors [1]. Rothman proposed a model which defines a minimum set of conditions, characteristics, and events that inevitably generate the disease [2], whether by acting simultaneously or in sequence [1]. While some of the components involved in cancer etiology are well known [3,4], others, such as those discussed herewith, are less familiar.

The pioneering work of Barker et al. [5–7] on the association between low birth weight and increased risk of adult hypertension [5] and cardiovascular disease [6] led to the hypothesis that intrauterine and infantile growth failure due to undernutrition determines adult susceptibility to chronic diseases. The mechanism involved is presumed to be epigenetic [7]. This theory became the basis of the conceptual framework for developmental origins of health and disease (DOHaD) [8,9] which denoted vulnerable developmental stages throughout the life course during which stressors may have long-lasting impact on adult health. Both animal and human studies [10,11] have yielded data supporting the DOHaD paradigm. However, the association between prenatal and postnatal exposure to hunger and adult cancer incidence is less clear, and studies have yielded contradictory results.

2. The available data

Animal studies clearly demonstrate the protective effect of caloric restriction on cancer incidence [12] and it was hypothesized that a similar effect may exist in humans. Anorexia nervosa may partially mimic the conditions prevailing in animal studies, of lifelong caloric restriction and balanced diet, since patients often consume a low calorie diet even in remission. A recent study reported a significantly lower risk for breast cancer but higher risk for esophageal, lung, and liver cancer in anorexia nervosa patients, compared to population-based controls [13].

The long-term implications of transient, severely restricted and often unbalanced diet on humans were often studied in populations impacted by war and other man-made disasters.

2.1. Studies in non-Jewish populations

World War II (WWII) in Europe exposed many non-Jewish populations to periods of moderate to severe hunger and stress. In Norway the German occupation (1940–1945) caused a moderate reduction in calorie intake. Studies that investigated cancer incidence in cohorts born before and after WWII [14–18] mostly indicated positive associations between nutritional intake (based on ecological proxy variables) and risk for breast [14,15] and colorectal [16,17] cancer. One study, though, disclosed higher risk for breast cancer in women aged 10–19 y during WWII who lived in non-food producing (vs. food producing) areas in Norway (RR = 1.3, 95%CI 1.2–1.4, respectively). A similar but weaker effect had been observed for those aged 0–9 years [18].

The Dutch ‘hunger winter,’ caused by a food embargo imposed by the Nazi regime, lasted 9 months (9/1944–5/1945). The average daily caloric intake was dramatically reduced to 800 Kcal/person, but was balanced in terms of macronutrients. In a series of studies [19–21], no significant associations were reported between exposure to famine (based on ecological data) and prostate [19], breast [20], and colorectal [21] cancers. However, when personal exposure data were used, exposed (vs. non-exposed) women had a significantly higher risk of breast cancer (hazard ratio, HR = 1.5, 95%CI 1.1–2.0) [22]. The same researchers also reported significantly increased plasma levels of insulin-like growth factor 1 (IGF-1) binding globulins in the exposed group, a finding that contradicted the expected short-term response to starvation and that may explain the increased risk for breast cancer over time [23]. Interestingly, a more recent study that examined the relationship between body size, physical activity, early-life exposure to the ‘hunger winter,’ and associations with methylated IGF-1 binding protein (IGFBPs) genes in colorectal cancer, reported significantly inverse HRs in exposed (vs. non-exposed) subjects in the subgroups of 2 and 3 methylated IGFBP genes, implying that nutritional deprivation in early life may modify cancer risk in adulthood [24].

The inhabitants of Guernsey, a British Channel island occupied by the Germans in 1940, had an average daily caloric intake of 1200 kcal/person during the last year of the occupation. Breast cancer incidence in women aged 10–18 years in 1944 who remained on the island during the occupation was non-significantly elevated (HR = 1.4, 95%CI 0.6–2.8) [25] compared to the incidence in those who were evacuated.

The siege of Leningrad began on September 1941. For a period of 28 months the city residents experienced severe starvation, with an average daily intake of 300 kcal/person and with virtually no protein at the height of the siege. Higher rates of female breast cancer mortality were observed in residents who remained in the city during the siege vs. those who were evacuated, (HR = 2.5, 95% CI 0.9–6.8), reaching statistical significance in those who were 10–18 years of age at the peak of the siege (1941–2): HR = 9.9, 95% CI 1.1–86.5 [26].

The Chinese famine during the Great Leap Forward (1958–1961) caused the deaths of 23–55 million people, mostly in rural areas. A study focusing on participants in a breast screening program in the Shanghai area revealed a higher incidence of both in-situ and invasive breast cancer in those born during the years of the famine (1959–1961) compared to earlier (1955–1958) and later (1963–1966) birth cohorts, but the hazard ratios were not statistically significant [27].

2.2. Studies in Jewish Holocaust survivors

The Jewish survivors of the Nazi regime, whether as captives in concentration/death camps or escapees living in the woods or in disguise among non-Jews often experienced near-starvation diets (200–800 kcal/person/day in concentration camps), extreme physical and mental stress, forced labor, and exposure to the elements and to infections [28]. Several studies of Israeli Holocaust survivors, whose exposure was typically longer and harsher than that of other populations, were undertaken.

The first study was based on a cohort that included all European Jews born between 1920 and 1945 who immigrated to Israel before (‘non-exposed’) or after (‘exposed’) WWII. Based on data from the Israel National Cancer Registry, it was found that exposure (vs. non-exposure) was associated with a significant increase in incidence in all-site cancer in men (relative risks, RRs = 1.2–3.5 in different birth cohorts) and women (RRs = 1.3–2.3), with an age gradient such that the strongest associations were observed in the youngest birth cohort. Increased risk was also observed for breast (women), colorectal (both sexes), and lung (men) cancer, with an age gradient found for the first two cancer types [29]. Notably, the findings for the oldest male birth cohort (born 1920–1924) for all-site cancer (RR = 1.2, 95%CI 1.1–1.2) [29] were confirmed by a later study which provided lengthy follow-up on a cohort of Jewish males with data on personal risk factors. In this study, using a model that adjusted for smoking and socioeconomic status and considered mortality from all causes as a competing risk, exposure (vs. non-exposure) was associated with an increased risk of all-site cancer (HR = 1.2, 95%CI 1.0–1.4)[30].

An additional cohort study compared individuals who were granted compensation for their war-time ordeals versus those denied such compensation, and included a complementary analysis comparing survivors from countries occupied by the Nazis with survivors from non-occupied countries. Both analyses revealed significantly increased risks for cancer: HR = 1.1 (p < 0.001) for those who were granted (versus denied) compensation and HR = 1.1 (p = 0.07) for those born in occupied (versus non-occupied) European countries. Increased hazards were also observed for colorectal and lung cancers, but not for breast cancer in females [31]. In contrast, in a case-control study of Holocaust survivors who lived under the Nazi regime in Europe for at least 6 consecutive months, 65 breast cancer patients, and 200 population-based female controls were interviewed, and their level of deprived nutrition and of symptoms of WWII-related post-traumatic stress disorder (PTSD) was compared. Interestingly, exposure to severe hunger (vs. mild) during WWII was significantly associated with breast cancer (OR = 5.0, 95%CI 2.3–10.8) [32] and WWII-related PTSD seemed to play a modifying role in this association [33].

Recently, a retrospective cohort study of all relevant members of Clalit Health Services, the largest healthcare fund in Israel covering approximately 55% of the total population, confirmed, based on direct and proxy exposure variables, that Holocaust survivors were at significantly increased risk for colon (HR = 1.9 and 1.3 in males and females, respectively), bladder (1.6 and 1.4, respectively), lung (1.9 and 1.4, respectively), malignant melanoma (1.2 and 1.3, respectively), breast (1.2 in women), and prostate (1.4 in men) cancers[34].

Finally, two cross-sectional studies focused on child Holocaust survivors (born in 1940–1945 during WWII), who had been exposed both pre- and postnatally [35,36]. One study reported higher prevalence of cancer in the exposed group (vs. controls): 30.0% vs. 8.7%, p < 0.001 [35], while the other observed no difference in cancer prevalence [36].

3. Conclusions

Studies show unequivocally that restricted diet in lab animals reduces cancer risk. Observational studies in non-Jewish European populations yielded mixed results which may be attributed to differing study types, definitions of exposure, the selection of control subjects, the nature of the exposure etc. In contrast, most studies of Holocaust survivors clearly indicated an inverse effect despite differing methodologies. Although these findings need consolidation, there are grounds for believing that exposure to hunger and stress under extreme situations may cause a cascade of epigenetic, hormonal, and biological changes that eventually modify cancer risk. Thus, exposed individuals should be regarded as a high risk group for cancer. Holocaust survivors are one example of such a group; these conclusions may be generalized to many populations around the globe, including, for example, the survivors of the civil war in Syria.

4. Potential implications

Individuals exposed to extreme and prolonged physical, mental, and nutritional hardships, and their health care providers, should be educated about the potential for an increased risk of cancer. Active primary and secondary (e.g. cancer screening programs) prevention measures should be encouraged and applied.

Furthermore, the possibility of transgenerational effects should be seriously considered. In this respect, the findings of Yehuda et al. [37,38] that parental Holocaust experiences and related PTSD caused specific epigenetic changes in offspring are of extreme importance. Thus, primary prevention strategies (i.e. the promotion of a healthy lifestyle) in offspring should be encouraged.

Future studies addressing these issues in those directly exposed and the ‘second generation’ should adopt the molecular pathological epidemiology approach[39] which may decipher interactions of environmental and lifestyle exposures with molecular pathologies and immune system abnormalities with respect to carcinogenesis.

Declaration of interests

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.