Background
Cancer may follow exposure to an environmental agent after many decades. The bacterium Helicobacter pylori, known to be acquired early in life, increases risk for gastric adenocarcinoma, but other factors are also important. In this study, we considered whether early-life family structure affects the risk of later developing gastric cancer among H. pylori+ men.
Methods and Findings
We examined a long-term cohort of Japanese-American men followed for 28 y, and performed a nested case-control study among those carrying H. pylori or the subset carrying the most virulent cagA+ H. pylori strains to address whether family structure predicted cancer development. We found that among the men who were H. pylori+ and/or cagA+ (it is possible to be cagA+ and H. pylori− if the H. pylori test is falsely negative), belonging to a large sibship or higher birth order was associated with a significantly increased risk of developing gastric adenocarcinoma late in life. For those with cagA+ strains, the risk of developing gastric cancer was more than twice as high (odds ratio 2.2; 95% confidence interval 1.2–4.0) among those in a sibship of seven or more individuals than in a sibship of between one and three persons.
Conclusions
These results provide evidence that early-life social environment plays a significant role in risk of microbially induced malignancies expressing five to eight decades later, and these findings lead to new models to explain these interactions.
This study suggests that early-life social environment has a significant role in risk of microbially induced malignancies such as gastric adenocarcinoma occuring five to eight decades later.
Editors' Summary
Background.
Although the theory that certain cancers might be caused by infectious agents (such as bacteria and viruses) has been around for some time, concrete evidence linking specific cancers and infections is only recently beginning to emerge. There is now very good evidence that stomach cancer, once one of the frequent types worldwide but now less common, is strongly associated with a particular infection of the stomach lining. This specific bacterium colonizing the stomach, Helicobacter pylori (or H. pylori), often infects people early in childhood through close contact with other people, and tends to stay in the body throughout life. However, most people do not suffer any symptoms as a result of being colonized with H. pylori. Researchers are interested in the relationship between stomach cancer and aspects of someone's upbringing, for example whether an individual has a large number of sisters and brothers and whether they are the youngest or oldest in a large group of siblings. One reason for being interested in this topic is that if H. pylori is mainly spread from one child to another in the home, we might expect children from large sibling groups, and the youngest children in a group, to be at greater risk of being infected, and then more likely to get stomach cancer later in life. Furthermore—and this was the primary reason for the study—the researchers wished to determine whether, among H. pylori+ people, the structure of the family affects the risk of developing stomach cancer much later in life. With all study participants being H. pylori+, the essential comparison was between people of high and low birth order.
Why Was This Study Done?
This group of researchers had already done a previous study that had shown that people who carry H. pylori in their stomachs are more likely to get stomach cancer, and also that younger children in a sibling group are more likely to get stomach cancer. In the period following that study, the examined population has become older and more of the people concerned have developed stomach cancer. This meant that the researchers could go back and extend their previous work to see, more reliably, whether stomach cancer was linked to family structure. It also meant that the researchers could look at the effects of each factor not only in isolation, but also the combined effect of all the different factors. The researchers also stratified for the most virulent strains (those that were cagA+).
What Did the Researchers Do and Find?
In this study, the researchers started out with a pool of 7,429 Japanese-American men living in Hawaii, USA, who had donated blood samples between 1967 and 1975. Of these men, 261 eventually developed stomach cancer. Each of the 261 men was then matched with a similarly aged man from the original pool of 7,429 men who did not have stomach cancer. The researchers then went back to the original blood samples taken many years before and tested the samples to see if the men were infected with H. pylori at the time the sample was taken and, if so, whether a particular strain of the bacterium, cagA, was present. The researchers then looked at whether the risk of getting stomach cancer was associated with the number of siblings a man had and whether he was older or younger than the other siblings.
Similar to the prior study, they found that men who had stomach cancer were three times more likely to carry H. pylori compared to men who did not develop stomach cancer. In men who had H. pylori, those with large numbers of siblings were more likely to get stomach cancer, and this was especially true for men who had the cagA strain of H. pylori. In the whole group of men with cancer, the order of birth (whether a man was older or younger in his sibling group) did not seem to be particularly linked to development of stomach cancer. However, in men who had the cagA strain of H. pylori, those from the largest sibships were at highest risk of developing gastric cancer; in this group, one particular type of cancer (the most common type—intestinal-type gastric cancer) was also associated with later birth order.
What Do These Findings Mean?
The researchers initially thought that men with H. pylori would be at a higher risk of getting stomach cancer if they had a large number of sisters and brothers, and especially if they were a younger sibling in a large group. This idea was supported by their data. These findings support the idea that people often get H. pylori from their older sisters and brothers, but there is not conclusive proof of this. There might be some other factor that explains the association between large family size and stomach cancer, for example that people from large families might be poorer and more at risk from stomach cancer for some other reason. Currently, most doctors do not recommend routinely testing people without any symptoms to see if they have H. pylori, but people with pain or discomfort in the upper abdomen would generally be screened for H. pylori and then treated to eliminate the infection if it is found. The main novel idea is that those people who are born in a large sibship, and/or are of higher birth order, are more likely to acquire their H. pylori from a genetically related person (a sibling) than from an unrelated person (friend/classmate). This “family-structure effect” could be the explanation as to why there is a higher risk of stomach cancer developing later—the strain from a genetically related person already is “preadapted” to the new host, and has a “head-start” on immunity, compared to a strain from an unrelated person. The researchers hypothesize that it is the nature of that initial interaction with the host that sets the stage for the kind of events that lead to cancers decades later.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040007.
A Perspective article by Dimitrios Trichopoulos and Pagona Lagiou discusses these findings further
MedLine Plus encyclopedia entry on stomach cancer
Wikipedia entry on Helicobacter pylori (Wikipedia is an internet encyclopedia that anyone can edit)
The US National Cancer Institute publishes information about stomach cancer
