Dr. Sharma's Obesity Notes

Regular readers of these pages are probably well aware of the increasing data on the importance of obesity as a risk factor for cancers.

This is particularly true for hormone-sensitive cancers like post-menopausal breast and ovarian cancer, which are significantly more common in women with excess weight. In addition, excess weight appears to negatively affect the prognosis and recurrence of these cancers irrespective of menopausal status.

One of the key genetic factors associated with breast and ovarian cancers is the tumor suppressor gene BRCA1, which plays an important role in DNA repair. Women who carry mutations in this gene have a 80% lifetime risk of breast cancer - but reduced activity of BRCA1 has also been found in cancers of women who do not carry BRCA1 mutations.

So can excess weight modify expression of BRCA1?

A new study by Li-Jun Di and colleagues from the US National Cancer Institute, Bethesda, ML, published in the latest issue of Nature Structural & Molecular Biology, now shows that the expression of the BRCA1 is regulated by a co-repressor and metabolic sensor called C terminal-binding protein (CtBP), which is in turn regulated by energy levels in a cell.

Simply put, when cells see too many calories, CtBP can switch off BRCA1 thereby negatively influencing DNA repair.

This situation is particularly harmful for tissues like the breast or ovaries which, in obesity, are at the same time stimulated by excess activation of estrogen in fat tissue.

Thus, excess weight not only causes breast and ovarian tissue to grow but at the same time it indirectly inhibits one of the key DNA repair molecules, thereby making it far more likely that mutations will cause malignant growth of these cells.

As recently discussed in another post, this is another example that the strong link between excess weight and cancers may not lie in the excess weight causing genetic defects, but rather in the weight affecting important repair mechanisms that would normally protect against cancers.

These observations certainly help explain the dramatic decrease in cancer risk seen with intentional weight loss in patients undergoing bariatric surgery.

AMS
Toronto, Ontario (in transit)

Di LJ, Fernandez AG, De Siervi A, Longo DL, & Gardner K (2010). Transcriptional regulation of BRCA1 expression by a metabolic switch. Nature structural & molecular biology PMID: 21102443

Metastasizing Cancer Cell

Later today, I will be presenting an overview of the etiological assessment and management of obesity in a plenary session also featuring Eric Westman (USA), speaking on low-carbohydrate interventions, and Jim Levine (USA), speaking on non-exercise activity thermogenesis (NEAT).

I also have the privilege of chairing a poster session on adipose tissue and inflammation.

But this morning, I attended a session devoted to obesity, diabetes and cancer.

As regular readers will be well aware, obesity accounts for almost 30% of all cancers - and one of the main reasons why bariatric surgery reduces mortality is because of its profound effect on cancer-related mortality.

Regarding the potential molecular link between excess weight and cancers, Jeff Holly (UK), spoke about the important role of metabolic pathways in determining cancer risk.

As Holly pointed out, we all carry countless gene mutations that are potentially cancerogenic in many of our cells (e.g. in the skin, colon, prostate, etc.) and that the number of these cancerous cells increases dramatically with age.

Fortunately, however, we also have very effective systems that keep these cancerous cells in check, which is why most of these cancer cells never develop into clinical disease.

Nevertheless, we know that these defense mechanisms can be substantially influenced by environmental factors. Thus, for e.g. migration and adoption studies show that moving into a western lifestyle, can quickly increase the risk of cancer, not by increasing the number of gene mutations, but rather by affecting the mechanisms that normally keep these early cancerous growths in check.

Even in studies on highly penetrant cancers like breast cancers caused by BRCA mutations, the actual development of clinical cancer varies with environmental exposure.

In his talk, Holly reviewed the role of the insulin-signaling pathway, which also appears to play a key role in tumorgenesis pathways. A key molecule here is Insulin-like Growth Factor (IGF) -1, higher levels of which appear to be associated with higher risk of cancer.

IGF-1 levels can be affected by many environmental factors, which affect genes involved in metabolic pathways relevant to cancer growth.

But substrate availability may also be important. Thus, in vitro studies show that high lipid and glucose levels can both promote the growth of cancerous cells and/or reduce their sensitivity to chemotherapeutic agents.

In summary, metabolic pathways can play a key role in promoting growth of the many pre-cancerous cells - thereby increasing the risk of these cells growing into clinical cancer. This of course provides a sound rationale for the observation that lifestyle factors can have such an important role in reducing the risk of cancers.

Following this presentation, I was particularly delighted to listen to Tobias Pischon from the German Institute of Nutrtition (DIFE), Potsdam-Rehbrucke, further discussing the association between obesity and cancer. Tobias, incidentally, is a former student of mine, whose MD thesis I had the privilege of supervising, before he went off to spend time at the Harvard School of Public Health.

Pischon pointed out that the link between obesity and cancer is not just related to excess weight, but rather to the presence of abdominal obesity, which readers will know, is the kind of fat distribution that is most relevant for the metabolic complications of excess weight.

Thus, as for cardiovascular and metabolic risk, BMI is not the best measure of cancer risk, but rather, increased cancer risk is far ore closely related to waist circumference (a surrogate for abdominal obesity). In fact, as Pischon demonstrated on the large EPIC data set, adding waist circumference to BMI resulted in a much better prediction of cancer risk than using BMI alone.

Thus, I guess if we continue to call obesity a “lifestyle” disease, I guess we can only say the same for most common cancers.

I herewith officially coin the term “lifestyle cancers” - a term that I am sure many people with cancer or cancer-survivors would probably not like to be labelled with (in the same manner that people with obesity don’t like the term “lifestyle” associated with their condition).

AMS
Stockholm, Sweden

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Overweight and obesity are now increasingly recognized as a major driver of cancers in the Western world. For example, recent estimates suggest that almost 1 in 3 cases of breast cancer are related to excess weight.

A new study, published last month in Lancet Oncology, by Christine Parr and colleagues from the Asia-Pacific Cohort Studies Collaboration now confirms a significant association between excess weight and cancer mortality across this region of the world.

The study includes data from over 400,000 participants from various populations from Asia and from Australia and New Zealand (ANZ).

Compared to individuals with normal weight, a BMI of over 30 was associated with a 1.21-fold increased risk for for all-cause cancer (excluding lung and upper aerodigestive tract), 1.50-fold increased risk for colon cancer, 1.68-fold higher risk for rectum cancer, 1.63-fold higher risk for breast cancer in women 60 years or older, 2.62-fold higher risk for ovary cancer, 4.21-fold higher risk for for cervix cancer, 1.45-fold higher risk for prostate cancer, and 1.66-fold higher risk for for leukaemia.

In contrast, excess weight did not appear to be associated with cancers of the oropharynx and larynx.

Given the recent dramatic rise in the prevalence of overweight and obesity in the Asia-Pacific region, home to a considerable proportion of the world population, it can only be expected that cancer mortality will likely place a significant health burden in this region of the world.

In light of the accumulating evidence that weight management and intentional weight loss can significantly reduce cancer mortality, this study calls for increased measures to both prevent and treat obesity in Asia-Pacific countries.

AMS
Edmonton, Alberta

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Parr CL, Batty GD, Lam TH, Barzi F, Fang X, Ho SC, Jee SH, Ansary-Moghaddam A, Jamrozik K, Ueshima H, Woodward M, Huxley RR, & on behalf of the Asia-Pacific Cohort Studies Collaboration (2010). Body-mass index and cancer mortality in the Asia-Pacific Cohort Studies Collaboration: pooled analyses of 424 519 participants. The lancet oncology, 11 (8), 741-752 PMID: 20594911

While most people often think of excess weight as a risk factor for diabetes, heart disease, sleep apnea, or osteoarthritis, an accumulating body of evidence now points to obesity an important risk factor for cancers.

While previous studies have shown the importance of obesity as a risk factor for breast and colon cancers, a study by Arsian and colleagues from the Pancreatic Cancer Cohort Consortium (PanScan) published in the latest issue of the Archives of Internal Medicine suggests that obesity may also be an important risk factor for pancreatic cancer.

Using a nested case-control design that included 2170 cases and 2209 control subjects, the PanScan study found a positive 33% higher risk for pancreatic cancer in individuals with the highest compared to the lowest BMI quartile. This relationship was found both in men and women.

When the researchers looked at abdominal obesity, the risk for pancreatic cancer in women in the highest quartile of waist circumference was almost twice that of women in the lowest quartile.

These findings certainly provide strong support for a positive association between BMI and pancreatic cancer risk and suggest that centralized fat distribution may increase pancreatic cancer risk, especially in women.

Given the observation that one of the most impressive impacts of bariatric surgery is an almost 60% reduction in cancer mortality, prevention of weight gain or successful weight management may certainly go a long way in reducing the risk of dying of this horrible disease.

AMS
Edmonton, Alberta

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Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB, Fuchs CS, Gross MD, Jacobs EJ, Lacroix AZ, Petersen GM, Stolzenberg-Solomon RZ, Zheng W, Albanes D, Amundadottir L, Bamlet WR, Barricarte A, Bingham SA, Boeing H, Boutron-Ruault MC, Buring JE, Chanock SJ, Clipp S, Gaziano JM, Giovannucci EL, Hankinson SE, Hartge P, Hoover RN, Hunter DJ, Hutchinson A, Jacobs KB, Kraft P, Lynch SM, Manjer J, Manson JE, McTiernan A, McWilliams RR, Mendelsohn JB, Michaud DS, Palli D, Rohan TE, Slimani N, Thomas G, Tjønneland A, Tobias GS, Trichopoulos D, Virtamo J, Wolpin BM, Yu K, Zeleniuch-Jacquotte A, Patel AV, & Pancreatic Cancer Cohort Consortium (PanScan) (2010). Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Archives of internal medicine, 170 (9), 791-802 PMID: 20458087

While I am taking a brief break from clinics and other obligations (including daily blog posts), I will be reposting past articles, which I still believe to be relevant but may have escaped the attention of the 100s of new readers who have signed up in the past months.

The following was first posted on 04/22/08

Yesterday’s big news was the study by Kerry Courneya, professor and Canada Research Chair in Physical Activity and Cancer at the University of Alberta, published in CANCER.

I am not going to repeat the findings or the data here because this was nicely summarized by Sharon Kirkey from Canwest News Service in the Edmonton Journal.

The bottom line is that cancer survivors are apparently not exercising more or eating healthier than everyone else, and are therefore at least as, if not even more, likely to develop obesity than the average Canadian.

This is particularly true for survivors of breast and colon cancer, which are particularly likely to recur with lack of physical activity, unhealthy eating and weight gain.

The dramatic impact of weight on cancer risk is perhaps best demonstrated by the observation that obesity surgery, which on average reduces body weight by 25%, results in an almost 60% reduction in cancer mortality! (see Adams et al. for an example of such a study).

I guess it just goes to show that cancer survivors are no less susceptible to the consequences of our obesogenic environment, which certainly does not make weight control easy, even at the best of times.

That is of course, unless there is something special about surviving cancer that makes you more likely to gain weight - an interesting hypothesis pursued by other researchers here at the University of Alberta.

I can think of a number of reasons why surviving cancer could predispose to weight gain: “catch-up” fat, depression, “post-traumatic” stress, anxiety, susbtance abuse, “overfeeding”, immobility, medications, and perhaps a few others.

Whatever the reasons, it looks like we may now need intervention programs to specifically address weight gain and obesity in cancer survivors?

For one, educating cancer survivors about the links between excess weight and cancer would be a start.

My sense is that most people still don’t fully appreciate the close link between obesity and cancer - all the more reason to promote healthy eating and active living for all.

Obesity prevention (and treatment?) may well turn out to be the most effective cancer prevention strategy (short of smoking cessation) - looks like a whole new field for bariatric health professionals?

I guess we’d call them Bariatric Oncologists?

AMS
Edmonton, Alberta