Clinicians will soon be able to use gene panel testing to identify those most at risk from developing breast cancer, thanks to 2,000 DNA samples gathered in Ireland and which were used as part of an international study involving more than 113,000 women, Peter Doyle reports

There are nine specific genes associated with breast cancer risk, according to the results of an international project with significant Irish involvement. The University of Cambridge-led BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing) study aimed to identify women at high risk of breast cancer and to develop sensitive and informative gene panel testing for the prediction of breast cancer risk.

During gene panel testing, specific genes linked to a particular genetic condition are examined at the same time.

BRIDGES investigators had used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls.

In separate analyses for protein-truncating variants and rare missense variants in these genes, they also estimated odds ratios for breast cancer overall and tumour subtypes and evaluated missense-variant associations according to domain and classification of pathogenicity.

DNA samples collected from 2,000 Irish patients and controls as part of NUI Galways Breast Cancer in Galway Genetics Study (BIGGS) also contributed to the findings of the paper, which were published in the January 2021 edition of the New England Journal of Medicine (Breast Cancer Risk Genes Association Analysis in More than 113,000 Women; NEJM, doi: 10.1056/NEJMoa1913948).

Contributing author Prof. Michael Kerin, Chair of Surgery at NUI Galway, Director of the Cancer Managed Clinical Academic Network for Saolta University Health Care Group, along with Dr Nicola Miller, Lecturer in NUI Galways School of Medicine, has directed the BIGGS since 2008.

With this (BRIDGES) study we can identify members within families, who have a higher risk of getting breast cancer, and then can avail of breast cancer reduction strategies, such as risk reduction surgery, in order to ensure they dont get the disease, Prof. Kerin said.

Dr Miller added that the some of the funding for the research had originated from breast cancer charities.

This work highlights the importance of collaboration in breast cancer research in the generation of data of global significance, she said.

It helps to better define the genes associated with breast cancer risk. While we cant change the genes we inherit, this knowledge will benefit patients undergoing genetic testing for breast-cancer susceptibility. We gratefully acknowledge the ongoing support of the National Breast Cancer Research Institute for funding the Irish contribution of this study.

Prof. Michael Kerin. Photo: Kelvin Gilmor

Writing in the NEJM, BRIDGES investigators said that genetic testing for cancer susceptibility was an established part of medical practice.

But, until recently, testing was performed mainly in patients with a strong family history of cancer and involved a limited number of genes known to be associated with a high risk of cancer or with specific cancer syndromes.

With the advent of affordable sequencing, testing with larger panels of genes has become possible, they wrote.

However, for many genes on such panels, evidence of an association with cancer is often weak and accurate estimates of the cancer risks associated with variants are often not available.

To better define the set of genes associated with breast cancer risk, they designed a panel consisting of 34 known or suspected breast cancer susceptibility genes and which included genes provided on commercial panels.

The data from the study was subsequently used to estimate the risks of breast cancer overall and tumour subtypes associated with germline protein-truncating variants, and rare missense variants in these genes.

The primary analyses were burden analyses in which odds ratios and 95 per cent confidence intervals for breast cancer associated with the presence of any variant in a given category were estimated by means of logistic regression, investigators wrote.

The two main categories were protein-truncating variants and rare missense variants (i.e., variants with a population frequency of <0.001). Missense-variant associations were evaluated according to domain and classification of pathogenicity. Analyses were also conducted according to tumour subtype, age, and ancestry (European vs. Asian).

The results showed that protein-truncating variants in five genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a significant risk of breast cancer overall.

There was more modest evidence of an association with breast cancer overall for protein-truncating variants in seven other genes: BARD1, RAD51C, RAD51D, PTEN, NF1, TP53, and MSH6.

For four of these genes (BARD1, RAD51C, RAD51D, and TP53), the Bayesian false-discovery probability was less than 0.05.

Commenting on the results, investigators said that they found strong evidence of an association with breast cancer risk (Bayesian false-discovery probability, <0.05) for protein-truncating variants in nine genes: ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53.

The data, however, varied according to the location of study participants; while in the population-based studies, odds ratios decreased significantly with increasing age for six genes BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP5.

Among European women, approximately 6.8 per cent of the patients and 2 per cent of the controls had protein-truncating variants in any of the nine genes associated with breast cancer risk; in addition, 2.2 per cent of the patients and 1.4 per cent of the controls had missense variants in CHEK2, investigators noted.

The frequency of protein-truncating variants among Asian women (4.4 per cent of the patients and 1.3 per cent of the controls) was lower than the frequency among European women; this finding is attributable to the much lower frequency of the c.1100delC variant in CHEK2 among Asian women.

For carriers of protein-truncating variants in BRCA1, BRCA2, and PALB2, the estimated absolute risks by 80 years of age exceeded the 30 per cent threshold for high risk, as defined by National Institute for Health and Care Excellence guidelines.

Investigators said that their findings may be used to guide screening, as well as prevention with risk-reducing surgery or medication, in accordance with national guidelines.

The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counselling, they explained.

The absolute risk estimates place protein-truncating variants in BRCA1, BRCA2, and PALB2 in the high-risk category and place protein-truncating variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in the moderate-risk category.

But they cautioned that because breast cancer risk was influenced by other genetic and lifestyle factors, in addition to family history, the incorporation of this information into risk models would be required to give appropriate estimates.

Despite the size of this study, the evidence of an association with breast cancer risk for several of the genes we analysed (e.g., FANCM, MSH6, and NF1) remains equivocal, and even for the genes that had a clear association with risk, the confidence intervals for the risk estimates are wide, they concluded.

Incorporation of pedigree data and combined analyses with other studies may improve the precision of these estimates. In the meantime, these results may help to guide the clinical reporting of results generated by multigene-panel testing and the counselling of women who are undergoing genetic testing for breast cancer susceptibility.

Prof. Kerin also said that he wanted to thank all the patients who have allowed investigators to use their tissue and blood samples in these studies.

One of the things that strikes me as a clinician is that almost never have I been refused participation in a research study, by any patient that I ask, and believe me I ask them all, he said.

And most people are very glad to be able to contribute something that helps people other than themselves.

Read more:
Using gene testing to assess the risk of breast cancer - Irish Medical Times

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