New Breast Cancer Risk Gene Variants

Below we see some new studies in which new genetic variants that increase breast cancer risk have been discovered.  Such findings have multiple long-term benefits.  First, to identify at-risk patients, who can then have additional screenings, earlier screening, etc.  Second, to understand the mechanisms by which these variants, or the genes linked to them (if the variants themselves are just "markers" of risk), affect breast cancer, so as to devise new preventive and therapeutic approaches.  Third, to combine points one and two, to devise individualized screening and prevention (and therapy?) regimens for specific individuals.

Paper one; abstract:

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Paper two; abstract:

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Physical Activity Can Affect Genetic Susceptibility To Weight Gain

By Javierlayus - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15900701

One often hears the excuse that genes makes someone overweight (note of course that humans have not undergone some sort of rapid genetic change precipitating the obesity epidemic).  It is therefore useful to know that a study has shown that to the extent that genetic differences between people can influence weight gain, that the weight gain can be "diminished by increasing physical activity."  Of course, controlling diet is usually the greatest factor in weight control, even taking genetic differences into account.  Again, genetic differences influencing weight gain have always existed; the skyrocketing expansion of waistlines and BMIs cannot be attributed to genetics as the major factor. Excerpted from the abstract:

Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown…In the combined cohorts, 4-year BMI change per 10-risk allele increment was -0.02 kg/m2 among participants with greatest increase in physical activity and 0.24 kg/m2 among those with greatest decrease in physical activity (P[interaction]<0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P[interaction]=0.001). Similar but marginal interactions were observed for the BMI-GRS (P[interaction]=0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.

Lifestyle versus predisposition: scratching my head

Have you heard about the health care systems in the U.S. that have started to sequence millions of genomes in order to unearth a few predisposition genes? Millions of dollars are now poured into this endeavor. As a result, we will eventually connect the presence of some gene variants with increased risk of conditions X, Y and Z, ... and we will know that Joe Smith carries a predisposition gene for condition Z.

The fact that these are only PREDISPOSITION genes tells you that LIFESTYLE may or may not allow for conditions X, Y, and Z to be developed. Then the logical question is, why are we so complacent about our current disease-permissive lifestyle? Should not we tackle unhealthy habits with the same enthusiasm (and the same amount of funds/resources) as the ones with which we embark on massive sequencing efforts? Is it cost-effective to allow the average American to play DARE by practicing the most disease-permissive lifestyle in the history of humankind?

Under ideal circumstances, in taking care of each individual, the health care system should combine the implementation of healthy habits along with the knowledge of the predisposition genes of the individual. Platforms such as PatientsLikeMe should match sequencing data input with physical/physiological data and health markers/outcomes. Prospective analyses of such data will suggest how "tweaks" in the lifestyle can prevent the establishment of conditions to which some are predisposed.

Since we are faraway from the ideal situation, it seems that educating the Americans in healthy prevention-oriented lifestyle is more economically sound than massive sequencing of a million human genomes. What do you think?