Only some genes count in breast cancer panels

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.