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Genetic Testing May Inflate Cancer Risk Estimates 

Cancer risk assessed by genome sequencing may give misleadingly high estimates if family history is not taken into account, according to a new study from the University of Exeter. The researchers pointed out that inflated risks from genetic testing alone could influence people to undergo unnecessary surgery.

They explained that genetic testing for BRCA1 and BRCA2 is offered to women with breast or ovarian cancer and/or a known history of hereditary breast/ovarian cancer, and if positive, chemoprevention or prophylactic mastectomy/ oophorectomy may be advised.

Similarly, patients with colorectal cancer are offered screening for hereditary non-polyposis colorectal cancer (Lynch syndrome), and a positive result may lead to regular colonoscopies or prophylactic surgery.

Home DNA Test Kits Used by People Without Cancer Links

However, the risk of cancer in these situations has mainly been calculated from cohorts of individuals already at high risk. These did not necessarily translate to the general population, now that many people pay for home DNA testing kits, or are given results from genetic research, without any personal link with cancer.

The Exeter team set out to investigate how penetrance of familial cancer genes varied with family history among 454,712 UK Biobank participants aged 40 to 69 who had exome sequence and clinical data collected between 2006 and 2021.

The study, published in the Lancet journal eClinicalMedicine, found that carrying a disease-causing BRCA variant was linked to risks of developing breast cancer before age 60 of 17.9% (CI 13.8–23.0) for BRCA2 and 22.8% (CI 15.9–32.0) for BRCA1. The risks attributable to having a close relative with breast or ovarian cancer were 24.1% (CI 17.5–32.6) and 44.7% (CI 32.2–59.3), respectively. 

Relative hazard ratios of carrying the pathogenic BRCA1 or BRCAvariants were 10.3 and 7.8, respectively, among women with a first-degree family history, but 7.2 and 4.7 in those without.

Previous Risk Estimates Based on High Risk Groups

Co-author Caroline Wright, professor of genomic medicine at the University of Exeter, said: "Our findings will not just apply to breast and colorectal cancer. All risk estimates of genetic disease have so far largely been based on relatively high-risk groups who attend specialist clinics, so they will not necessarily translate to the general population." She cautioned that the finding had "important ramifications for population screening using genome sequencing". 

Lead author Dr Leigh Jackson, lecturer in genomic medicine at the university, said that more women were choosing to have prophylactic mastectomy in the wake of actress Angelina Jolie's highly publicised decision to do so. However, informed decisions could be swayed by the risk level presented. He urged that "anyone communicating cancer risk does so based on a detailed family history, not just genetics alone". 

The researchers found similar results with Lynch syndrome. Participants with a pathogenic MLH1, MSH2 or MSH6 variant had increased risks of colorectal cancer that were significantly higher in those with a family history (relative hazard 35.6, 48.0, and 9.9, respectively) than those without (13.0, 15.4, and 7.2). Penetrance to age 60 was also higher for carriers of pathogenic MLH1 or MSH2

variants with a family history (30.9%, CI 18.1–49.3, and 38.3%, CI 21.5–61.8) versus those without (20.5% CI 9.6–40.5 and 8.3% CI 2.1–30.4), though not significantly so among people carrying MSH6 (6.5% versus 8.3% respectively). 

This difference in penetrance in carrier individuals could be sufficient to impact on eligibility for specialist clinical care, the team pointed out. For example the NICE threshold for referral to a specialist genetic clinic for people with familial breast cancer requires ≥30% lifetime risk. On the other hand, genetic screening for these conditions in the general population could result in many people being exposed to needless scans or further procedures.

Important to Consider all Relevant Information 

Asked to comment by Medscape News UK, Dr Lyndsy Ambler, senior strategic evidence manager at Cancer Research UK, said: "This research contributes to our understanding of cancer risk and highlights the importance of considering all relevant information when making decisions about healthcare. 

"More research is needed to understand if and how these findings should inform changes to current practice."

Also commenting to Medscape News UK, Dr Kotryna Temcinaite, head of research communications at Breast Cancer Now, said: "While we’ve long known that people who’ve inherited an altered BRCA1 or BRCA2 gene are at an increased risk of breast cancer, this new research suggests the severity of this risk depends on whether they have a close family member, like a parent or a sibling, who has been diagnosed with the disease.

"People with an altered BRCA gene but no family history of breast cancer may have a much lower chance of developing the disease than previously thought. Though home genetic testing kits are now widely available, it’s crucial that anyone with concerns about their family history of breast cancer speaks to their GP for further assessment of their individual level of risk."

The study was funded by the Medical Research Council.

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