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Contribution of the PALB2 c.2323C>T [p.Q775X] Founder mutation in well-defined breast and/or ovarian cancer families and unselected ovarian cancer cases of French Canadian descent
© Tischkowitz et al.; licensee BioMed Central Ltd. 2013
Received: 10 September 2012
Accepted: 3 January 2013
Published: 9 January 2013
The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population.
We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes.
We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52.
Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population.
KeywordsPALB2 p.Q775X p.Q775* Hereditary breast cancer Breast cancer risk Ovarian cancer Founder mutations French Canadians
Carriers of PALB2 mutations in a heterozygous state have been associated with increasing the risk of developing breast cancer [1–10]. PALB2 is a partner and localizer of the BRCA2 breast-ovarian cancer susceptibility protein to DNA damage sites [9, 11]. Penetrance estimation for conferring breast cancer risk has been hampered by the paucity of cases, although estimates of 2- to 6-fold increased risk to breast cancer have been suggested [12, 13], thus classifying PALB2 as a moderate breast cancer risk allele [9, 12–14]. Germline mutations in PALB2 have also been identified in familial pancreatic cancer [15, 16]. PALB2 is comprised of 13 exons spanning a 38 kb region on chromosome 16p12.1 and mutation screening is complicated by the diversity of variants (including missense mutations) identified in cancer cases. The PALB2 c.2323C>T mutation, which results in the introduction of a stop codon at amino acid position 775 (p.Q775X), has been reported in at least three French Canadian breast cancer families , and along with other protein truncating PALB2 mutations found in breast cancer cases, is strongly suspected to be deleterious . The French Canadian population of Quebec exhibits an unique genetic demography [18–20]. About 40% of French Canadian cancer families with at least three cases of breast and/ovarian cancer carry a pathogenic BRCA1 or BRCA2 mutation [20–25]. Although 15 different mutations in these genes have been reported in French Canadian cancer families, six specific mutations in BRCA1 and BRCA2 have been shown to account for a significant majority of mutation-positive families [20–26]. This has been attributed to a shared ancestry of mutation carriers due to common founders of the French Canadian population of Quebec [25–28].
The number of PALB2 p.Q775X mutation-positive cases that have been reported thus far in studies involving the French Canadian population vary according to criteria and catchment area of ascertainment of index breast cases tested [5, 29]. To further assess the contribution of PALB2 p.Q775X mutation in the French Canadian population, we report the results of screening this variant in 71 well defined cancer families with at least three confirmed cases of breast and/ovarian cancer found negative for the most common BRCA1 and BRCA2 mutation reported in this population. We report the cancer phenotype of a new p.Q775X mutation-positive family. We also report the screening 385 invasive ovarian cancer cases and 106 low malignancy potential ovarian tumors not selected for family history of cancer that were ascertained from the French Canadian population, and describe the cancer history of the p.Q775X cases identified in this screen. We describe our findings in the context of previous studies describing mutation screens of PALB2 in individuals of French Canadian descent.
Subjects and cancer families
Families and features of index cases screened for PALB2 c.2323C>T [p.Q775X] variant
Features of ovarian tumors examined for PALB2 c.2323C>T [p.Q775X] mutation
Number of cases
Prior history of BC
Low malignant potential
Low malignant potential
Low malignant potential
Mutation analysis was performed on DNA extracted from peripheral blood leukocytes or from fresh frozen tumor tissue. A sequence analysis of protein coding exons of PALB2 for the index cases of 14 families was performed as described previously [5, 10, 17] (Table 1). The targeted analysis for PALB2 c.2323C>T (p.Q775X) variant was performed using an allelic specific assay as described . The variant-positive cases were confirmed by DNA sequencing using 3730XL DNA analyzer system platform from Applied Biosystems (Carlbad, CA, USA) at the McGill University and Genome Quebec Innovation Centre (Montreal, PQ, CDN). Sequences were compared with PALB2 NCBI Reference Sequence NM_024675 as described in GenBank (http://www.ncbi.nlm.nih.gov). For the Loss of heterozygosity (LOH) analysis, fresh frozen ovarian tumor tissue from the PALB2 p.Q775X mutation-positive case was macrodissected and DNA was extracted from the collected cells using the QIAamp DNA Mini Kit (Qiagen). The PCR was carried out in a volume of 50 μL, as previously described [5, 10]. Sequence data were analyzed using the Lasergene SeqMan Pro sequence analysis software by DNASTAR, Inc. (Madison, WI, USA) and Chromas 2.31 from Technelysium Pty Ltd. (Helensvale, Australia) and compared to the sequences from lymphocyte DNA from PALB2 p.Q775X mutation-positive and mutation-negative cases.
The PALB2 p.Q775X variant is also annotated as p.Q775* according to a recently proposed nomenclature alteration for nonsense changes by the Human Genome Variation Society (http://www.hgvs.org). However for historical purposes the p.Q775X designation is maintained in this report.
PALB2c.2323C>T [p.Q775X] carriers in breast and/or ovarian cancer families
One PALB2 p.Q775X positive case was identified among the cancer families not previously investigated for PALB2 mutations. The index carrier case was identified among the total of 48 (2.1%) HBC families or 71 (1.4%) HBC and HBOC families that share a phenotype defined by at least three or more confirmed cases of breast and/or ovarian cancer in the same familial branch (Table 1). These families were previously found negative for BRCA1 and BRCA2 mutations or the most common pathogenic mutations in these genes found in the French Canadian population.
PALB2c.2323C>T [p.Q775X] carriers in ovarian cancer cases
One PALB2 p.Q775X positive case was identified among the 491 women with ovarian cancer or low malignant potential tumors. The carrier was diagnosed with a papillary serous cystadenocarcinoma at age 58. The carrier was identified among the 385 (0.3%) invasive ovarian carcinomas of all histopathological subtypes and among 238 (0.4%) invasive serous ovarian carcinomas (Table 2).
Summary of PALB2 c. 2323C>T [p.Q775X] carriers identified in studies of French Canadian cancer families or cases
p.Q775X positive cases
Features of p.Q775X positive case [Family number]
Number of index cases screened
Context and feature of cases or families tested
HBC and HBOC families; BRCAPRO scores > 0.10
HBC and HBOC families; BRCAPRO scores < 0.10
BC 54 [P280311 and (F15732)]
BC < 50 years of age, or BC between 50–65 yrs of age with at least one other BC or OC in first or second degree relative
BC 36 [P260071] BC 49 [P310301]
BC <50 years
Common French Canadian mutation negative
BC 36 [P260071] BC 46 [P280311] BC 49 [P310301] BC 49 [P36470]
BC <50 years
Common French Canadian mutation negative
High risk BC families
HBC and HBOC families with at least 2 first/second degree relatives with BC
BiBC 39–42 [F1469]
HBC families (see Table 1)
Mutation-negative or common French Canadian mutation negative
HBOC families (see Table 1)
Mutation-negative or common French Canadian mutation negative
OC (see Table 2)
In contrast, no PALB2 variants were reported in two other independent studies involving 99  and 21  independently ascertained breast cancer families of French Canadian descent. Genealogy and genetic studies have reported variability of founder effects in various regions of Quebec , suggesting that demography may also be a factor in the paucity of PALB2 p.Q775X carriers in some studies of French Canadian cancer families. The majority of our cases were ascertained in Montreal , whereas independent groups have ascertained their families from the Quebec City region . This possibility could also account for the lack of PALB2 p.Q775X carriers found in a screen of 6,440 newborns of French Canadian descent as the majority of these newborns were from the Quebec City region .
The young ages of breast cancer diagnoses and number of breast cancer cases per family in PALB2 p.Q775X carrier families suggest that carriers of this mutation are at high risk for breast cancer (Table 3), as has been posited with some PALB2 mutation carrier families [5, 10, 17]. Our findings here support this notion, as the PALB2 p.Q775X carrier identified had a bilateral case of breast cancer diagnosed before age 45 years and a strong family history of breast cancer (Figure 1).
It is interesting that the PALB2 p.Q775X carrier found among the ovarian cancer cases examined in this study had a prior history of breast cancer (Table 3). Notable is that her personal history of cancer does not match any of the cases that appear in the pedigrees of PALB2 p.Q775X positive French Canadian cancer families described thus far (including the new carrier family identified in this study). The role of PALB2 in ovarian cancer is uncertain, as there have been few documented ovarian carcinoma cases harboring germline mutations in this gene. Two PALB2 mutation carriers were identified in a study of 339 unrelated ovarian cancer cases of Polish descent . The carriers had high grade carcinomas of different histopathological types: serous (case diagnosed at 61 years) and endometrioid (case diagnosed at 54 years) subtypes, where the latter carrier also harbored a BRCA2 mutation . Two (0.6%) PALB2 mutation carriers were reported in a study of 360 ovarian cancer cases that were also screened for BRCA1, BRCA2 and other recently described cancer susceptibility genes . Neither of these two high-grade serous carcinoma PALB2 mutation-carriers (diagnosed at ages 51 and 58) had a personal history of breast cancer, although the ovarian cancer case diagnosed at age 58 years had a family history of breast and/or ovarian cancer . A low frequency of PALB2 carriers (0.4%) was also recently reported in an investigation of 253 ovarian cancer cases from the Volga-Ural region of Russia , with the only carrier identified in this study having a bilateral (moderate grade) serous ovarian carcinoma at age 46 and a prior history of melanoma. The low frequency of PALB2 mutation carriers identified thus far may argue a minor role for this gene in conferring ovarian cancer risk compared with higher frequency of mutation carriers observed in breast cancer cases and breast cancer families. This is consistent with recent findings estimating that PALB2 heterozygotes were 1.3-fold more likely to have a relative with ovarian cancer in the context of HBOC family history .
Our genetic analyses of the carrier ovarian cancer specimen harboring the PALB2 p.Q775X mutation did not exhibit evidence of LOH of the PALB2 locus. This could also be consistent with sufficient contamination of normal stromal DNA such that it would obscure an imbalance of alleles. It has been suggested that PALB2 contributes to carcinogenesis through haploinsufficiency and/or a dominant negative effect given the paucity of LOH observed in the majority of breast cancer cases from PALB2 carriers [3, 4, 6, 10], with the exception of one study where a high frequency of LOH was seen . LOH was observed for both ovarian cancer cases identified in one study . Promoter methylation silencing has also been reported in four of 53 sporadic ovarian cancer cases . The significance of these findings is unknown and warrants further investigation to elucidate the role of PALB2 in both breast and ovarian carcinogenesis.
The PALB2 c.2323C>T [p. Q775X] mutation confers increased risk for breast cancer in the French Canadian population of Quebec. The contribution of PALB2 c.2323C>T [p. Q775X] to the causation of breast cancer in French-Canadians appears to be lesser than that attributable to the most common founder alleles in BRCA1 and BRCA2, but the young age at diagnoses and associated familial history of breast cancer suggest that this variant should be added to the panel of deleterious mutations screened for assessing breast cancer risk in this unique population. Indeed during the preparation of this manuscript another PALB2 carrier harboring the p.Q775X variant was identified in the Hereditary Cancer Clinics affiliated with McGill University Health Centre. The carrier had bilateral breast cancer at ages 34 and 42 years and a strong family history of breast cancer further supporting the notion that PALB2 p.Q775X carriers are at increased risk for breast cancer.
We thank Lise Portelance and Suzanna L. Arcand for technical assistance. We also thank Laura Palma for providing information about a newly identified mutation positive proband. We acknowledge the Banque de tissus et de données of the RRCancer of the Fonds recherche Québec Santé (FRQS) which is affiliated with the Canadian Tumour Repository Network (CRTNet) for providing specimens from cancer families. The Research Institute of the McGill University Health Centre and the Centre de recherche du Centre hospitalier de l′Université de Montréal receive support from the FRQS. Marc Tischkowitz a recipient of the FRQS clinician-scientist award. This research was supported in part by a grant from the Cancer Research Society to Patricia N. Tonin, from grants from the Canadian Breast Cancer Research Alliance, Jewish General Hospital Weekend to End Breast Cancer and the Quebec Ministry of Economic Development to Marc Tischkowitz, and from a grant from the Susan G. Komen for the Cure to William D. Foulkes.
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