The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Abstract

The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

Keywords: French Canadian; breast cancer; cancer predisposing gene; hereditary cancer syndrome; ovarian cancer.

Figure 1

Representative carrier frequencies of frequently occurring pathogenic variants in HBC and HBOC predisposing genes in French Canadians of Quebec. Distribution of BRCA1 and BRCA2 variants in hereditary breast cancer syndrome (a), hereditary breast and ovarian cancer syndrome (b), and sporadic ovarian cancer cases (c). Carrier frequency of a PALB2 variant (d) and TP53 variants (f) in hereditary breast cancer. Carrier frequency of a PALB2 variant (e) and a RAD51D variant (g) in sporadic ovarian cancer cases. Data from [35] where 169 cancer families were analyzed. Selected variants in BRCA1 (n = 11) and BRCA2 (n = 9) were assessed in this study.Data from [39] where 439 sporadic ovarian cancer cases were analyzed. Selected variants in BRCA1 (n = 2) and BRCA2 (n = 4) were assessed in this study. Data from [40] where 48 hereditary breast cancer families and 238 sporadic serous ovarian cancer cases were analyzed. One PALB2 variant (c.2323C > T; p.Gln775Ter) was assessed in this study. Data from [41] where 52 hereditary breast cancer families were analyzed. Targeted sequencing of TP53 exons and splice sites was assessed. Data from [42] where 341 sporadic high-grade serous ovarian cancer cases were analyzed. One RAD51D variant (c.620C > T; p.Ser207Leu) was assessed in this study. Sporadic ovarian cancer cases are all derived from the same study group [39].

Figure 2

The most frequently occurring pathogenic variants BRCA1, BRCA2, PALB2, and RAD51D in French Canadians of Quebec and their allele frequency in other worldwide non-cancer populations. Source of the data: gnomAD v2.1.1 (gnomad.broadinstitute.org).

Figure 3

Pathogenic variants and variants of uncertain significance reported in French Canadians of Quebec mapped to full length BRCA1 (a) or BRCA2 (b) transcripts. Variants are predicted to be pathogenic or have uncertain significance based on ClinVar and/or ACMG guidelines. RING = Really Interesting New Gene domain; NES = Nuclear export signal; NLS = Nuclear localization signal (BRCA1: [92]; BRCA2: [93]); SCD = Serine cluster domain [94]; BRCT = BRCA1 C Terminus domain; BRC repeats = BRCA2 repeats; HD = Helical domain; OB = Oligonucleotide binding; Tower = Domain essential for DNA binding [95]. BRCA1 GenBank: AAC37594.1 [96], BRCA2 GenBank: AAB07223.1 [97], DNA binding domain [98]. See Table S2 for more information about variants.