Familial Cancer Risk Complex, Not Limited to Same Site

Liam Davenport

May 05, 2023

Certain relatives of women with early-onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients' siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients' siblings had a significantly increased risk of testicular and ovarian cancers.

"The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular and pancreatic cancers, as well as beyond first-degree relatives," the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland, say. "Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied."

Erin F. Cobain, MD, who was not involved in the research, said the findings are "not very surprising to me."

Cobain said that at her institution, she has seen "many, many cases" of family members of early-onset breast cancer patients with discordant cancers "where we are unable to find a clear genetic cause."

Not being able to find an identifiable cause for the clustering of early-onset cancers can be "very frustrating" for patients and their families, said Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer on April 19.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is "unclear whether the familial risk is limited to early-onset cancer of the same site," the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and 31 December 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands' families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio [SIR], 0.99; 95% CI, 0.84–1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05–1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68–1.25).

And siblings' children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97–1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because "registry data do not include comprehensive information on the gene mutation carriage status." But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Cobain noted as well that the current study is potentially limited by its "very homogeneous" cohort.

But, overall, the findings indicate that familial risk is often "a much more complicated problem, mathematically and statistically," than were there a single genetic culprit, Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

"Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual's cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk," she added. However, "we're starting to get there."

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Cobain had no relevant financial relationships to declare.

Int J Cancer. Published online April 19, 2023. Full text

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