Stratified comorbidities reflect known cancer pathogenesis and mechanisms. In this section, we study the comorbidity relationships between cancers and individual diseases in two disease classes—nervous system diseases and endocrine, nutritional, and metabolic disease. We choose these disease classes, since they contain the largest number of diseases, and their comorbidity relationships with cancers are less likely to be over-estimated compared with other disease classes.

We extracted 14 nervous system diseases from the top-ranked comorbidities in all age groups. Among them, anxiety, depression, and epilepsy are associated with cancers at most age levels; schizophrenia and bipolar disease tend to co-occur with cancers among patients younger than 60 years (Fig. 5).

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Gender has little impact on the comorbidity patterns of these diseases. Note that other mental problems, such as Alzheimer’s disease and Parkinson’s disease, do not have strong associations with cancers in any patient group, although both diseases are com­mon among elderly patients in our data.

Previous studies have demonstrated that they are inverse cancer comorbidities.28,29

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Literature evidences support the frequent co-occurrence of cancers with depression,30–32 anxiety,33,34 and epilepsy.35,36

A few studies link their roles as cancer comorbidities with the impaired immune responses37,38: they found that multiple molecular immunological factors are compromised in chronic stress and depression, and these factors later contribute to the development and progression of some types of cancers.

On the other hand, cancers also increase the risk of these nervous system disorders. For example, cancer patients who have developed brain metastases have greater risk of epilepsy.35

For the association between cancers and serious mental illness, such as bipolar disorder, a recent study supports the increasing risk of cancers among bipolar disorder and schizophrenia patients.39 This study also pointed out that the cancer incidence among patients with mental illness is relevant to their ages.

We repeated the same analysis on 16 endocrine, nutri­tional, and metabolic disorders. In most age groups, particularly patients older than 20 years, cancers frequently co-occur with metabolic syndrome components, such as hypercholesterolemia and hyperlipidemia; endocrine system diseases, such as hypothyroidism and hypokalemia; and diabetes mellitus (Fig. 6). 

Their cancer comorbidity patterns are independent of patient gender. Literature evidences show that several factors can explain the observed comorbidity between metabolic disorders and cancers. First, environment factors contribute to the disease comorbidity relationship.

Previous studies show that metabolic disorders increase the risk of cancers, and the patients share similar lifestyles, such as high fat dietary and few exercises, with cancer patients.40,41

Second, common molecular mechanisms also play roles in explaining the disease comorbidity relationship. It was also demonstrated that insulin resistance, which contributes to the development of metabolic syndrome and type 2 diabetes, has associations with colon cancer.42,43

In addition, osteoporosis tends to occur among elderly cancer patients (Fig. 6). Researches on the link between osteoporosis and breast cancer show that elderly cancer patients are more likely to have lower estrogens, which has a protective effect on bone, and reduced the risk of bone loss.44

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Study of colorectal cancer comorbidities generated novel hypotheses. Colorectal cancer is deadly, complex, and common around the world. We currently lack the knowledge to completely understand the mechanisms of colorectal cancer.45

We applied our approach and extracted comorbidities for colorectal cancer. In the random walk with restart algorithm, we selected “colorectal cancer,” “colorectal cancer recurrent,” and “colorectal cancer metastatic” as the seeds. Since no patients younger than 40 years have colorectal cancer in our data, we only show results of the three elderly patient groups.

A total of 44 diseases of 6 classes associate with colorectal cancer across different age groups. These disease classes include the following: digestive system disorders, cardiovascular diseases, inflammatory disorders, metabolic diseases, respiration diseases, and nervous system disorders.

We further investigated the metabolic diseases in detail, since this class contains the largest number of diseases as colorectal cancer comorbidities. Figure 7 shows part of the metabolic diseases that are strongly associated with colorectal cancer. Hypercholesterolemia, hypothyroidism, and diabetes mellitus have comorbidity associations with colorectal cancer in all age groups, although the strengths of the associations tend to decrease when ages increase.

Gender has little impact on the comorbidity patterns of these three diseases. A large number of literature evidences support that metabolic syndrome and type 2 diabetes are among the risk factors of colorectal cancer.46,47 Researches also have demonstrated that insulin resistance may explain the co-occurrence between colorectal cancer and type 2 diabetes.48,49

In addition, osteoporosis is associated with colorectal cancer among elderly female patients. A recent retrospective study50 confirmed our result and demonstrated that osteoporosis may increase the risk of colorectal cancer among postmenopausal women. Another study also showed that an osteoporosis oral drug reduced the risk of colorectal cancer.51

Currently, the molecular basis that contributes to the observed comorbidity association between osteoporosis and colorectal cancer is not yet clear. Studies on the common molecular mechanisms between the two diseases have the potential to discover new knowledge.