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. 2024 Sep 27;14(10):1034.
doi: 10.3390/jpm14101034.

Implementing the Risk Stratification and Clinical Management of Breast Cancer Families Using Polygenic Risk Score Evaluation: A Pilot Study

Barbara Rizzacasa  1 , Vanessa Nicolì  1 , Chantal Tancredi  1 , Chiara Conte  2 , Leila B Salehi  2 , Miriam Lucia Carriero  1 , Giuliana Longo  3 , Vincenzo Cirigliano  3 , Luis Izquierdo Lopez  3 , Bibiana Palao  3 , Ilaria Portarena  4 , Oreste Claudio Buonomo  5 , Giuseppe Novelli  1 , Michela Biancolella  6
Affiliations

Implementing the Risk Stratification and Clinical Management of Breast Cancer Families Using Polygenic Risk Score Evaluation: A Pilot Study

Barbara Rizzacasa et al. J Pers Med. .

Abstract

Background: The identification of women at high risk of breast cancer (BC) is crucial for personalized screening strategies. Pathogenic and likely pathogenic variants (PVs/LPVs) in susceptibility risk genes explain part of the individual risk. Moreover, a polygenic background, summarized as a polygenic risk score (PRS), contributes to the risk of BC and may modify the individual risk in carrier and non-carrier members of BC families.

Methods: We performed a retrospective pilot study evaluating PRS in women from a subset of high- (BRCA1 and BRCA2) and moderate-risk (PALB2 and ATM) BC families. We included PVs/LPVs carriers and non-carriers and evaluated a PRS based on 577,113 BC-associated variants. Using BOADICEA, we calculated the adjusted lifetime BC risk.

Results: Our data showed that in BRCA1/BRCA2 carriers, PVs have a major role in stratifying the lifetime risk, while PRS improves risk estimation in non-carriers of these families. A different scenario may be observed in PALB2 and ATM families where PRS combined with PV/LPV carrier status gives a more informative lifetime risk.

Conclusions: This study showed that in BC families, the PRS might help to quantify the weight of the genetic familial background, improving the individual risk stratification and contributing to personalized clinical management for carrier and non-carrier women.

Keywords: ATM; BRCA1; BRCA2; PALB2; PRS; breast cancer; polygenic risk score.

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Conflict of interest statement

The authors (B.R., V.N., C.T., M.L.C., C.C., L.B.S., I.P., O.C.B., G.N., and M.B.) declare no conflicts of interest. The authors (G.L., V.C., L.I.L., B.P.) are affiliated with Veritas Intercontinental. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
(A) Family tree; in red are shown the BC-affected individuals. The black arrow indicates the proband. Carrier status is mentioned in the figure, where +/− indicates the presence of the PV in heterozygous while −/− indicates the absence of the variant. (B) The table shows the polygenic risk score (PRS) obtained using myHealthScore test by Veritas Intercontinental and the evaluation of the overall BC risk calculated by age 80 without and with PRS using BOADICEA model. Family proband is reported in bold, and family members considered for the BOADICEA analysis are marked with “*”. NA (Not applicable) for subjects older than 80 years of age at the moment of the analysis. (C) Graphical representation of the percentage risk of developing BC (breast cancer) or CBC (contralateral breast cancer) during lifetime in BRCA1 family members. The blue line corresponds to the individual personal risk. Green dot line indicates the estimated risk of CBC in BC affected women population. Gray dot line indicates the estimated risk of BC in the general population.
Figure 2
Figure 2
(A) Family tree; in red are shown the BC-affected individuals, while in light blue are shown subjects affected by both breast and ovarian cancers. The black arrow indicates the proband. Carrier status is mentioned in the figure, where +/− indicates the presence of the PV in heterozygous while −/− indicates the absence of the variant. (B) The table shows the polygenic risk score (PRS) obtained using myHealthScore test by Veritas Intercontinental and the evaluation of the overall BC risk calculated without and with PRS using BOADICEA model. Family proband is reported in bold, and subjects considered for the BOADICEA analysis are marked with “*”. (C) Graphical representation of the percentage risk of developing BC (breast cancer) or CBC (contralateral breast cancer) during lifetime in BRCA2 family members. The blue line corresponds to the individual personal risk. Green dot line indicates the estimated risk of CBC in BC affected women population. Gray dot line indicates the estimated risk of BC in the general population.
Figure 3
Figure 3
(A) Family tree; in red are the BC-affected individuals. The black arrow indicates the family proband. Carrier status is mentioned in the figure, where +/− indicates the presence of the PV in heterozygous while −/− indicates the absence of the variant. (B) The table shows the polygenic risk score (PRS) obtained using myHealthScore test by Veritas Intercontinental and the evaluation of the overall BC risk calculated without and with PRS using BOADICEA model. Family proband is reported in bold, and subjects considered for the BOADICEA analysis are marked with “*”. (C) Graphical representation of the percentage risk of developing BC (breast cancer) or CBC (contralateral breast cancer) during lifetime in PALB2 family members. The blue line corresponds to the individual personal risk. Green dot line indicates the estimated risk of CBC in BC affected women population. Gray dot line indicates the estimated risk of BC in the general population.
Figure 4
Figure 4
(A) Family tree; in red are the BC-affected individuals. The black arrow indicates family proband. Carrier status is mentioned in the figure, where +/− indicates the presence of the PV in heterozygous while −/− indicates the absence of the variant. (B) The table shows the polygenic risk score (PRS) obtained using myHealthScore test by Veritas Intercontinental and the evaluation of the overall BC risk calculated without and with PRS using BOADICEA model. Family proband is reported in bold, and subjects considered for the BOADICE analysis are marked with “*”. (C) Graphical representation of the percentage risk of developing BC (breast cancer) or CBC (contralateral breast cancer) during lifetime in ATM family members. The blue line corresponds to the individual personal risk. Green dot line indicates the estimated risk of CBC in BC affected women population. Gray dot line indicates the estimated risk of BC in the general population.
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References

    1. Ferlay J., Ervik M., Lam F., Laversanne M., Colombet M., Mery L., Global Cancer Observatory: Cancer Today International Agency for Research on Cancer: Lyon, France. [(accessed on 30 May 2024)]. Available online: https://gco.iarc.who.int/today/
    1. Yoshida R. Hereditary Breast and Ovarian Cancer (HBOC): Review of Its Molecular Characteristics, Screening, Treatment, and Prognosis. Breast Cancer. 2021;28:1167–1180. doi: 10.1007/s12282-020-01148-2. - DOI - PMC - PubMed
    1. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L.M., Ding W. A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1. Science. 1994;266:66–71. doi: 10.1126/science.7545954. - DOI - PubMed
    1. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the Breast Cancer Susceptibility Gene BRCA2. Nature. 1995;378:789–792. doi: 10.1038/378789a0. - DOI - PubMed
    1. Renwick A., Thompson D., Seal S., Kelly P., Chagtai T., Ahmed M., North B., Jayatilake H., Barfoot R., Spanova K., et al. ATM Mutations That Cause Ataxia-Telangiectasia Are Breast Cancer Susceptibility Alleles. Nat. Genet. 2006;38:873–875. doi: 10.1038/ng1837. - DOI - PubMed

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