Families (and their histories) will always be vital for cancer risk assessment

Mary Beth TerryMary Beth Terry

My husband’s dad died of cancer. So did most of his uncles. On both sides. Should he be concerned? Of course. Family history is one of the strongest predictors of most cancers. Few risk factors increase cancer risk more than family history, with the exception of certain viruses and smoking. The increase in risk from family history is even greater if there are multiple individuals within a family with the same cancer and/or if the family members are diagnosed at an early age. The clustering of cancers within families has led to the identification of many causal cancer genes. Genetic testing for these known cancer genes has become the standard of cancer risk assessment for many individuals with a family history.

There is no doubt that testing for these cancer-related genes has improved our ability to identify individuals at greater risk of cancer and has helped in making clinical care decisions about primary prevention (e.g., chemoprevention or risk reducing surgeries) and secondary prevention (e.g., age and mode of cancer screening).

Even though many cancers cluster in families, most of these clusters remain unaccounted for by cancer-related genes.  Furthermore, many cancer genes have also been found to be mutated in individuals without a family history. This imperfect mapping of cancer genes to a family history of cancer has led to two major reactions, one in research and the other in clinical care.  In research it has led to the development of new and expanded technologies that can identify additional genes that may account for the pattern of cancers seen in some families. In clinical care, this imperfect mapping has led some to push for widespread genetic testing for all individuals regardless of family history so that no potential mutation is missed.

Both reactions reflect the view that family history will someday no longer be important.  Such a view cannot be reconciled with the growing body of evidence that the environment can modify cancer risk within families.  We have every reason to expect that shared family environment, which influences everything from our socioeconomic status and education,  the external carcinogens that we are exposed to in the neighbourhoods that we live in, to behavioural factors, including patterns of nutrition, physical activity, alcohol consumption and uptake of smoking, is one of the major explanations of why there still remains unexplained familial clustering of cancers. Nonetheless, rather than focus on how we can improve measurements of the environment and how the environment modifies our genetic susceptibility, we search for more genes.

A major public health consequence of the view that family history equals genes has been that many individuals with a family history of cancer are not informed that they can reduce  their risk by modifying environmental factors. To have a better gauge on the magnitude of cancer risk that can be modified within individuals with a family history of cancer, we need to prospectively study not just an individual in a family, but the entire family, including the environmental factors that they share. However, family-based cohorts remain rare.  At a minimum we need ways to better measure family history within epidemiological and clinical settings. In the past, researchers have been reluctant to include multiple family members within a given study because of the added statistical complications. These reservations are no longer valid as practically all statistical models can accommodate multiple members within a family, and there are now several pedigree programs that make it much easier to discover your family history.

As the accuracy of your family history improves and our gene testing panels are expanded, family history will become the main link to truly understand the interaction of the environment with cancer risk within families.  Thus, we have every reason to not eliminate family history information from the clinical and epidemiological record. In contrast, family history information will remain essential both for etiologic research as well as prevention research. As for my husband, it turns out all of the male members of the previous generation were heavy smokers. Thus, he has inherited the genes but not the modifier. At a population level as well as an individual level, we need to know our family histories and should heed the advice of the late, great Harper Lee:

“You can choose your friends but you sho’ can’t choose your family, an’ they’re still kin to you no matter whether you acknowledge ’em or not, and it makes you look right silly when you don’t.”    Harper Lee


Read more:

Themed issue on cancer epidemiology in the International Journal of Epidemiology.

Terry MB, Phillips KA, Daly MB, John EM, Andrulis IL, Buys SS, Goldgar DE, Knight JA, Whittemore AS, Chung WK, Apicella C, Hopper JL. Cohort Profile: The Breast Cancer Prospective Family Study Cohort (ProF-SC)Int J Epidemiol. 2015 Jul 13.

Pharoah PD, Day NE, Duffy S, Easton DF, Ponder BA.  Family history and the risk of breast cancer: a systematic review and meta-analysisInt J Cancer. 1997 May 29;71(5):800-9.

Matakidou A, Eisen T, Houlston RS. Systematic review of the relationship between family history and lung cancer risk. Br J Cancer. 2005 Oct 3;93(7):825-33.

Delgado-Cruzata L, Wu HC, Liao Y, Santella RM, Terry MB.  Differences in DNA methylation by extent of breast cancer family history in unaffected women. Epigenetics. 2014 Feb;9(2):243-8. doi: 10.4161/epi.26880. Epub 2013 Oct 29.

Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, Beeri R, Gal M, Grinshpun-Cohen J, Djemal K, Mandell JB, Lee MK, Beller U, Catane R, King MC, Levy-Lahad E.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14205-10. doi: 10.1073/pnas.1415979111.

Tehranifar P, Wu HC, Shriver T, Cloud AJ, Terry MB.  Validation of family cancer history data in high-risk families: the influence of cancer site, ethnicity, kinship degree, and multiple family reporters. Am J Epidemiol. 2015 Feb 1;181(3):204-12. doi: 10.1093/aje/kwu258. Epub 2015 Jan 7.


Mary Beth Terry focuses her research on breast cancer and in the molecular epidemiology and lifecourse methods of the disease, in particular. She is a cancer epidemiologist with over 15 years of leading studies of breast cancer etiology specifically focused on the role of genetics, epigenetics, and other biomarkers play in modifying the effects of environmental exposures.
She is a Professor of Epidemiology at the Mailman School of Public Health at Columbia University, and an Editor of the International Journal of Epidemiology.
Follow the Mailman School of Public Health on Twitter @ColumbiaMSPH.




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