Associations between family history of cancer and genes coding for metabolizing enzymes (United States).
OBJECTIVE
Family history of cancer has been a useful tool to identify highly penetrant genes. However, the association between family history and low-penetrance genes that are prevalent in the population, is less well understood. While epidemiologists have studied low-penetrance genes in association studies at the population level, geneticists have often favored family studies to identify low-penetrance genes in the same manner that these families have been used to identify high-penetrance genes. In this study, we evaluated the association between family history of cancer and molecular variants of three genes: N-acetyltransferases (NAT2), glutathione-S-transferases (GSTM-1), and methylenetetrahydrofolate reductase (MTHFR). These genes were examined because of their plausible functional significance and their association with cancer risk in some studies.


METHODS
In a large multi-centered study of colon cancer, reported family history of cancer in first-degree relatives was used to classify cases and controls separately as having a family history of colorectal cancer, hormone-related cancers, smoking-related cancers, prostate cancer, and any cancer.


RESULTS
With three weak exceptions, we did not observe significant associations between any of these genes and family history of cancer. The ability of family history to positively predict the presence of variants of low-penetrance genes that may carry an elevated risk ranged from 41% to 60%; low-penetrance variants accurately predicted a family history of cancer 9 to 17% of the time. Assessment of the likelihood of having a family history of cancer given the combination of genetic and environmental factors, showed that those who smoked 20 or more cigarettes per day were more likely to have a family history of a smoking-related cancer irrespective of genotype.


CONCLUSIONS
People with a family history of cancer are not more likely to have a variant of low-penetrance genes than those without a family history of cancer. Family studies may not be efficient methods to study low-penetrance genes.
Slattery
M L
ML
University of Utah Medical School, Salt Lake City, Utah 84132, USA.
Edwards
S L
SL
Samowitz
W
W
Potter
J
J
D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D005069:Evaluation Studies as Topic; D005192:Family Health; D005260:Female; D005796:Genes / Q000235:genetics*; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D014481:United States
D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors; C478900:NAT2 protein, human