Two recurrent pathogenic/likely pathogenic variants in PALB2 account for almost half of PALB2 positive families in Slovenia

doi:10.21203/rs.3.rs-4569442/v1

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Research Article

Two recurrent pathogenic/likely pathogenic variants in PALB2 account for almost half of PALB2 positive families in Slovenia

https://doi.org/10.21203/rs.3.rs-4569442/v1

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Introduction: The prevalence and spectrum of PALB2 pathogenic/likely pathogenic variants (PV/LPVs) may vary across different regions, and these have not yet been analysed and reported in Slovenian HBOC families.

Methods: We performed a retrospective analysis of all 5099 consecutively tested individuals from 4610 families who fulfilled national criteria for HBOC-panel testing from January 2015 to January 2022. After genetic counselling, genetic testing with next generation sequencing was performed for all probands and cascade testing was offered to their blood relatives.

Results: Among all probands tested 0.9% (40/4610) were PALB2 PV/LPV carriers. 14 different PALB2 PV/LPVs were detected, one of them was novel. Five PV/LPVs were found to be recurrent in Slovenian population with two most frequent being c.509_510del and c.1451T > A. Altogether, 61 individuals from 41 PALB2 positive families were identified, 43 being cancer patients. 27.9% PALB2-positive cancer patients were diagnosed with more than one malignant tumour. We identified three double heterozygote carriers with additional PV/LPVs in ATM, CHEK2 and BRCA1.

Discussion: This report provides the first comprehensive description of molecular and clinical characteristics of PALB2 carriers in Slovenia. The frequency of PALB2 pathogenic variants in the Slovenian HBOC accounts for 0.9% of all individuals tested for PVs in HBOC-related genes. Our study adds a novel recurrent mutation, which is unique to the Slovenian context and one PV/LPVs, which had not been reported in the literature so far. The results of our study add information on genotype and phenotype in PALB2-positive patients and may be used for population specific assessment.

Ethics approval: The present study was approved by the National Ethics Committee and the Institutional Ethics Committee of the Institute of Oncology Ljubljana (0120–591/2020/3 on the 20th of January 2021).

HBOC

PALB2

breast cancer

ovarian cancer

risk-reducing salpingoophorectomy

recurrent pathogenic variants

Cancer patients with suspected hereditary breast and ovarian cancer (HBOC) syndrome, along with their healthy relatives, can benefit from multigene panel testing. If they are identified as carriers of pathogenic/likely pathogenic variants (PV/LPVs) in high risk cancer genes, we may offer them prevention measures such as enhanced cancer surveillance and discuss risk reducing surgeries to lower cancer burden (Kapoor et al. 2015). Multigene panel testing may reveal not only PV/LPVs in BRCA1 and BRCA2 genes, but also in other HBOC -related genes.

For over a decade, it has been recognized that germline PV/LPVs in PALB2 (partner and localizer of BRCA2) are associated with an increased risk of breast cancer (BC) (Rahman et al. 2007). Germline PV/LPVs in PALB2 are reported in up to 1% of BRCA1/2 negative breast cancer patients (Wu et al. 2020; Woodward et al. 2021). Other malignancies, such as male breast cancer (Pritzlaff et al. 2017), ovarian cancer (OC), pancreatic cancer (PaC) (Hu and Guo 2020), prostate cancer, colorectal, and gastric cancer (Foulkes 2008) were also reported in carriers of germline PV/LPVs in PALB2. The risk estimates are, however, based on analysis of small patients’ cohorts, the existing literature presents conflicting data, and the statistical evidence remains weak. Notably, the largest study so far by Yang et al. on 524 families from 21 countries, demonstrated a substantial association between germline PALB2 PV/LPVs and ovarian cancer (RR 2.91), pancreatic cancer (RR 2.37), and male breast cancer (RR 7.34) (Yang et al. 2020a). Nevertheless, further studies are necessary to enhance our understanding.

The PALB2 gene encodes a protein that acts as a bridge between BRCA1 and BRCA2 proteins, playing a crucial role in homology-directed recombination DNA repair (Walsh 2015). There is some evidence that new targeted treatments, which are effective in BRCA1 and BRCA2 PV/LPV carriers (such as poly-ADP-ribose polymerase (PARP) inhibitors), are also effective in individuals with PALB2 PV/LPVs, which is unsurprising given the shared underlying biology (Castroviejo-Bermejo et al. 2018). Understanding an individual’s PALB2 mutation status is therefore essential for personalised management, not only in preventive setting, but also when making treatment decisions for these cancer patients.

The prevalence and spectrum of PV/LPVs may vary across different regions due to ethnic differences. Quantifying cancer risks associated with specific PV/LPVs and understanding the biological characteristics of malignancies in carriers with these variants is important for establishment of targeted clinical guidelines.

Institute of Oncology Ljubljana (IOL), where the study was conducted, is the principal national institution that supervises programs on comprehensive cancer care in Slovenia, which is a central European country with a population of two million. IOL offers cancer genetic counselling and genetic testing of high-risk individuals at the national level and therefore serves as a referral tertiary centre for the whole country.

In the Slovene HBOC cohort the prevalence and spectrum of germline PALB2 PV/LPVs have not yet been analysed and reported. Our study aimed to describe these PV/LPVs in PALB2 and analyse the types of cancer and age of cancer diagnosis in PALB2 PV/LPV carriers.

Patients

Multigene panel testing with next generation sequencing (NGS) for HBOC-related genes was introduced at the IOL in late 2014. The latest gene panel (in use since 2022) consists of nineteen genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53. A proband (an index case) was defined as a family member (usually an affected individual) through whom a family with a PV/LPV is ascertained. If a PV/LPV was diagnosed in at least two or more seemingly unrelated families, it was considered a recurrent variant. Our retrospective study group encompassed 5099 individuals (4564 females and 535 males) from 4610 HBOC families who underwent genetic counselling in our Cancer Genetics Clinic at the Institute of Oncology Ljubljana and were referred to germline genetic testing between January 2015 and January 2022.

Family history data was collected from all tested families and all cancer diagnoses were verified in the Slovenian Cancer Registry. The registry contains data of all cancer diagnoses since 1950, when compulsory reporting of cancer diagnosis started in Slovenia. Positive family history for HBOC syndrome was defined as a family history of at least one first- or second-degree relative with breast, ovarian, prostate, or pancreatic cancer. We disregarded cases of non-melanoma skin cancer and cervical cancer in the analysis.

Family members of carriers of PV/LPVs were offered either cascade genetic testing for known PV/LPV in the family or NGS panel testing in case they fulfilled the inclusion criteria for panel testing. If the tested individuals gave their consent to report secondary findings (reporting the finding of a PV/LPV not initially suspected), secondary findings were also reported according to the ACMG criteria (Richards et al. 2015). Patients who harboured variants of unknown significance were not included in the analysis.

All participants provided written informed consent. The present study was approved by the National Ethics Committee and the Institutional Ethics Committee of the Institute of Oncology Ljubljana (0120–591/2020/3 on the 20th of January 2021). Research was conducted according to the 1975 Helsinki Declaration as revised in 1983 and the procedures used met the ethical standards of these bodies.

DNA Extraction

DNA was isolated from blood samples according to the established laboratory protocol as previously published (16).

Next Generation Sequencing

Next generation sequencing (NGS) was performed on Illumina MiSeqDx Sequencing System using TruSight Cancer Panel or TruSight Hereditary Panel (Illumina, San Diego, CA, USA) to enrich and sequence all translated exons and ± 25 bp flanking intronic regions of all HBOC panel genes. Bioinformatics and copy number analysis were performed as described by our group previously (Gornjec et al. 2019; Klančar et al. 2020). Germline variants were classified for their clinical importance according to ACMG/AMP guidelines (Plon et al. 2008; den Dunnen et al. 2016). Variants are described according to HGVS v20.05 nomenclature (den Dunnen et al. 2016). Our HBOC gene panel included 19 genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53. For PALB2 reference sequence LRG_308t1 (NM_024675.3) was used. All PV/LPV germline variants in HBOC genes detected by NGS were additionally confirmed by Multiplex Ligation-dependent Probe Amplification analysis or Sanger sequencing as described by our group previously (Stegel et al. 2022).

Statistical Analysis

Statistical analysis was performed using SPSS software (version 25). We used descriptive statistics to describe patients’ clinical, pathological, and genetic characteristics.

Study cohort

From January 1st 2015 to January 31st 2022, 5099 individuals (535 males and 4564 females) from 4610 families were tested for germline PV/LPVs in HBOC-related genes. The median age of individuals at the time of testing was 54 years.

PV/LPV detection rate among 4610 tested probands/families

In 19.1% (883/4610) of tested families a germline PV/LPV in HBOC-related genes was detected. BRCA1 PV/LPVs were detected in 8.4% (386/4610). Additionally, PV/LPVs were detected in BRCA2 in 4.9% (224/4610) of all probands, in CHEK2 in 1.8% (83/4610), in ATM in 1.5% (69/4610) and in PALB2 in 0.9% (40/4610). The frequency of all PV/LPVs in HBOC-related genes is presented in Fig. 1.

PALB2 PV/LPVs were detected in 1.0% of all BRCA1/2 negative families (40/4000).

In 22 out of 883 (2.5%) families, probands were diagnosed with two PV/LPVs and in one family (0.1%) one proband was diagnosed with three PV/LPVs in the HBOC-related genes.

PALB2 study cohort

We identified PALB2 PV/LPVs carriers in 40 HBOC families. In the same period, one additional family was identified, where a PV/LPV was reported as a secondary finding when a male patient with gastric cancer was tested for Lynch syndrome. Our PALB2 positive cohort was therefore composed of 41 families. Within these 41 families, a total of 61 family members were identified as carriers of a PALB2 PV/LPV.

Spectrum of PALB2 PV/LPVs in the Slovenian cohort of 41 PALB2 positive families

We identified 14 different PALB2 PV/LPVs. PALB2 c.912 del p.(Val305*) had previously not been reported in the literature and was found in one proband (Table 1).

Five PV/LPVs were recurrent. The two most frequent were c.509_510del and c.1451T > A, detected in 10 different families each, together encompassing almost half (20/41, 48.8%) of all PV/LPVs detected in our population.

Table 1

Spectrum of *PALB2* PV/LPVs in the Slovenian population.
PALB2 PV/LPV type	Previously reported	ACMG/AMP and Variant class*	Variant Type	N of carriers	N of families (% of all families)
c.1451T > A p.(Leu484*)	yes	PV Class 5	nonsense	19	10 (24.5%)
c.509_510del p.(Arg170Ilefs*14)	yes	PV Class 5	frameshift	14	10 (24.5%)
c.1027C > T p.(Gln343*)	yes	PV Class 5	nonsense	8	6 (14.7%)
c.172_175del p.(Gln60Argfs*7)	yes	PV Class 5	frameshift	5	4 (9.8%)
c.3549C > G p.(Tyr1183*)	yes	LPV Class 4	nonsense	2	2 (4.9%)
c.1317del p.(Phe440Leufs*12)	yes	PV Class 5	frameshift	3	1 (2.4%)
c.1240C > T p.(Arg414*)	yes	PV Class 5	nonsense	3	1 (2.4%)
c.48G > A p.(Lys16=)	yes	PV Class 5	synonymous, splicing	1	1 (2.4%)
c.2192T > G p.(Leu731*)	yes	PV Class 5	nonsense	1	1 (2.4%)
c.1676_1677delinsG p.(Gln559Argfs*2)	yes	PV Class 5	frameshift	1	1 (2.4%)
c.3164dup p.(Tyr1055*)	yes	PV Class 5	nonsense	1	1 (2.4%)
deletion of exons 11–12 c.(3113 + 1_3114-1)_(3350 + 1_3351-1)del p.?	yes	PV Class 5	multiple exon deletion	1	1 (2.4%)
c.395del p.(Val132Alafs*45)	yes	PV Class 5	frameshift	1	1 (2.4%)
c.912del p.(Val305*)	no	PV Class 5	nonsense	1	1 (2.4%)
All PALB2 PV/LPVs				61	41 (100%)

Legend: PV/LPV = pathogenic variant/likely pathogenic variant, SNV = single nucleotide variation, BC = breast cancer, OC = ovarian cancer, NET = neuroendocrine tumor, PaC = pancreatic cancer, f = female, m = male, ACMG/AMP classification (12) classification system proposed by Plon et al. (15).

Cancer types diagnosed in PALB2 PV/LPV carriers

Out of the 61 PALB2-positive patients, 43 (70.5%) were diagnosed with at least one type of cancer (3 males, 40 females). The distribution of cancer types and ages at diagnosis are illustrated in Fig. 2. The median age at the diagnosis of the first malignancy was 47 years (range 32 years – 69 years).

Among 36 PALB2 positive BC (invasive and in situ) patients, 35 were females and one was male. The median age at BC diagnosis was 46.5 years, ranging from 32 years to 69 years. The median age at genetic testing was 51 years, ranging from 21 years – 79 years. Twelve different PV/LPVs were identified in PALB2 positive BC patients (Table 1 and Fig. 1).

Male carriers with cancer

Eight of the PALB2 carriers were male and three of them were diagnosed with one malignancy each: a carrier of PALB2 c.1027C > T p.(Gln343*) was diagnosed with BC at the age of 69, a carrier of PALB2 c.3549C > G p.(Tyr1183*) was diagnosed with pancreatic cancer at 45 years of age and a carrier of PALB2 c.2192T > G (p.Leu731*) was diagnosed with gastric cancer at 53 years of age.

Clinical Characteristics of double heterozygotes

Among PALB2 PV/LPV carriers, three patients were classified as double heterozygotes (DH). Their clinical characteristics are presented in Table 2.

Table 2

Characteristics of double heterozygotes.
Patient (sex)	PALB2 PV/LPV	Other HBOC gene PV/LPV	Cancer type (age at diagnosis)	Histopathological Characteristics
Patient 43 (f)	deletion of exons 11–12 c.(3113 + 1_3114-1)_(3350 + 1_3351-1)del p.?	ATM c.2413C > T p.(Arg805*)	BC (48)	poorly differentiated, bifocal, luminal B IDC
Patient 17 (f)	c.1451T > A p.(Leu484*)	CHEK2 c.1100del p.(Thr367Metfs*15)	BC (32)	poorly differentiated, triple negative IDC
Patient 42 (f)	c.912del p.(Val305*)	BRCA1 c.181T > G p.(Cys61Gly)	BC (42)	atypical medullary
			OC (57)	HGSC
			BC (67)	unknown histology
			PaC (69)	adenocarcinoma

Legend: PV/LPV = pathogenic variant/likely pathogenic variant, BC = breast cancer, OC = ovarian cancer, PaC = pancreatic cancer, HGSC = high-grade serous carcinoma, FIGO = the International Federation of Gynecology and Obstetrics, f = female, m = male.

Multiple primary cancers

In total, 12 out of 43 (27.9%) PALB2 positive patients with cancer were diagnosed with more than one malignant tumor. Among them, 7/12 had negative family history and 3/7 had their first cancer diagnosed after the age of 50 years. Median interval between first diagnosis and a new primary cancer was 8 years (range 1–18 years). Characteristics of patients with multiple primary malignancies are presented in Table 3.

Table 3

Characteristics of *PALB2* positive patients with multiple primary malignancies in different organs.
Patient (sex)	Patient with PV/LPVs	Type of Cancer (age at diagnosis)	Family history (number of affected family members)
Patient 33 (f)	PALB2 c.1240C > T p.(Arg414*)	melanoma (53), BC (56)	positive (1)
Patient 10 (f)	PALB2 c.509_510del p.(Arg170Ilefs*14)	papilla Vateri (56), fallopian tube (62)	negative
Patient 37 (f)	PALB2 c.1676_1677delinsG p.(Gln559Argfs*2)	melanoma (47), BC (48)	positive (1)
Patient 31 (f)	PALB2 c.172_175del p.(Gln60Argfs*7)	DCIS (49), NET origo ignota (67)	negative
Patient 42 (f)	PALB2 c.912del p.(Val305) BRCA1* c.181T > G p.(Cys61Gly)	BC (42, 67), OC (57), PaC (69)	positive (1)
Patient 1 (f)	PALB2 c.509_510del p.(Arg170Ilefs*14)	BC (49, 53)	positive (3)
Patient 7 (f)	PALB2 c.509_510del p.(Arg170Ilefs*14)	BC (44, 52)	negative
Patient 5 (f)	PALB2 c.509_510del p.(Arg170Ilefs*14)	BC (58, 62)	negative
Patient 9 (f)	PALB2 c.509_510del p.(Arg170Ilefs*14)	BC (36, 48)	negative
Patient 18 (f)	PALB2 c.1451T > A p.(Leu484*)	BC (52, 60)	negative
Patient 36 (f)	PALB2 c.1317del p.(Phe440Leufs*12)	BC (51), DCIS (52)	negative
Patient 30 (f)	PALB2 c.172_175del p.(Gln60Argfs*7)	BC (40, 57)	positive (2)
Legend: PV/LPV = pathogenic variant/likely pathogenic variant, BC = breast cancer, OC = ovarian cancer, DCIS = ductal carcinoma in situ, NET = neuroendocrine tumor, PaC = pancreatic cancer; f - female

As shown in Table 3, one carrier of PALB2 PV/LPV, who also harboured a BRCA1 PV/LPV, was diagnosed with four primary cancers: twice with BC (at 42 and 67 years), a high-grade serous carcinoma of the ovary (age at diagnosis 57) and a pancreatic adenocarcinoma (age at diagnosis 69). Additionally, two PALB2 positive patients both developed BC (aged 48 and 56, respectively) and melanoma (aged 47 and 53, respectively).

PALB2 positive carriers without cancer diagnosis

Our cohort of PALB2 PV/LPV carriers without a cancer diagnosis consisted of 18 individuals from 11 families. Thirteen were female and five were male. Two of them were identified through panel testing and 16 by cascade testing. Median age at genetic testing was 44 years (range 21 – to 75 years).

Among these individuals, PALB2 c.1451T > A p.(Leu484*) PV/LPV was found in 11 individuals from six families, PALB2 c.509_510del (p.(Arg170Ilefs14)) was found in two individuals from two different families, PALB2 c.1317del p.(Phe440Leufs12) was found in two individuals from the same family, and one individual was identified with each of the following PV/LPVs: PALB2 c.1240C > T p.(Arg414*), PALB2 c.1027C > T p.(Gln343*), and PALB2 c.172_175del p.(Gln60Argfs*7).

Having epidemiological data on the frequency and spectrum of germline PV/LPVs associated with different hereditary cancers is of the utmost importance for every country aiming to organize an optimal cancer prevention programme and optimize cancer patients’ management. In the Slovene population, data on the occurrence of germline PV/LPVs in BRCA1 and BRCA2 genes and the clinicopathological characteristics of malignancies in those patients, have already been reported (20). Additionally, the spectrum of BRCA1 and BRCA2 PV/LPVs in male breast cancer patients, and characteristics of breast cancer patients with CHEK2 PV/LPVs have been studied (Besic et al. 2008; Krajc et al. 2014; Cvelbar et al. 2017; Nizic-Kos et al. 2021). PALB2 is one of the most common HBOC-related genes, found in approximately 1% of BRCA1/2 negative BC patients (Wu et al. 2020; Woodward et al. 2021) and is highly penetrant (Yang et al. 2020b). Nevertheless, very little is known about the characteristics of carriers of PALB2 PV/LPVs and the clinicopathological characteristics of tumors diagnosed in these patients. This gap in knowledge underscores the importance of further research into PALB2-associated cancers, not only for specialized institutions but also for primary care physicians.

Detection rate and spectrum of PALB2 PV/LPVs

Among all families tested with HBOC panel, we identified at least one germline PV/LPV in one of the genes in 19.1%. PALB2 was the fifth most commonly mutated HBOC-related gene (following BRCA1, BRCA2, CHEK2 and ATM). PV/LPVs in PALB2 represent 0.9% of all individuals tested, which was expected as it had previously been reported that 0.2–0.9% of women with breast cancer who undergo genetic testing will carry germline PV/LPV in PALB2 (Hu et al. 2021).

In our cohort the frequency of PV/LPVs in more than one gene from the HBOC panel in tested individuals is 2.6% (23/883) and is higher than the one reported in the literature, where we can find data ranging from 0.5 to 1% (Rosenthal et al. 2017; Shao et al. 2020). That may be due to the high prevalence of recurrent PV/LPVs in our population (Krajc et al. 2008; Stegel et al. 2011; Krajc et al. 2014).

In 41 families 14 different PALB2 PV/LPVs were detected. PALB2 c.912 del p.(Val305*) had not been reported previously and was found in one proband. Newly described PALB2 PV/LPVs in patients with BC are important since they can contribute to international databases and patients may benefit from prevention and treatment options.

Recurrent PV/LPVs in PALB2 in the Slovenian population

Five PV/LPVs in PALB2 were recurrent (diagnosed in at least two or more seemingly unrelated families) in our population, with PALB2 c.509_510del and PALB2 c.1451T > A being the two most frequent, detected in 10 different families each, and together encompassing almost half (20/41 or 48.8%) of all detected PV/LPVs in our population. Recurrent PALB2 PV/LPVs have been reported in other populations as well, such as those from Argentina (Gonzalez et al. 2022), Finland (Erkko et al. 2007) and Poland (Noskowicz et al. 2014). PALB2 c.509_510del has been described by Noskowitz et al. as being present in about 1 in 400 unselected breast cancer patients from Central Europe (Germany) and Eastern Europe (Belarus, Russia) (Noskowicz et al. 2014). PALB2 c.509_510del has also been described as a recurrent mutation in BC and OC patients from Poland (Kluska et al. 2017). We found no reports on the presence of PALB2 c.509_510del in Western European, Asian or American populations. While the Slovenian language does belong to the South Slavic language group, genetic studies have revealed close genetic affiliations with West Slavic populations, such as Poles, suggesting a common Slavic ancestor originating from the Dnieper basin (Zupan et al. 2013). We found no genotype-phenotype correlation studies for this specific PV. Of note, three patients from our cohort (33.3%) were diagnosed with a metachronous contralateral BC, one additional (11.1%) with a metachronous contralateral and ipsilateral BC. Additionally, we found two cases of ovarian cancer (10.5% of PALB2 c.509_510delGA carriers) with a median age at diagnosis 56.5 years (range 51 years – 62 years), one case of carcinoma of the papilla Vateri and one malignant melanoma. Based on our data BC patients harbouring PALB2 c.509_510del are at high risk of developing a second BC and OC, making them high-risk group among PALB2 PV carriers.

PALB2 c.1451T > A has not yet been described as a recurrent mutation in any population in the literature, however it has been found in nineteen individuals from ten different families in our cohort, which makes it a unique recurrent mutation in the Slovenian population. Among nineteen carriers of the above-mentioned PV, eight were diagnosed with breast cancer, with a median age at diagnosis 49 years. While it is challenging to establish genotype-phenotype correlation, this information could still be valuable in everyday clinical practice and may be included in the studies with bigger sample sizes.

Malignancies among PALB2 PV/LPV carriers

It has been known for more than a decade that PALB2 PV/LPVs increase BC risk (Hamdan and Nowak 2022). The risk is 2–30 times higher than in the general population, depending on the type of PV/LPV, age, and family history and PALB2 is considered a high-penetrance susceptibility gene for BC (Antoniou et al. 2014). As expected, the most common malignancy diagnosed in our cohort was BC in 36 patients, which confirms this association. Recent research has strengthened the correlation between PALB2 PV/LPVs and ovarian cancer. Yang et al. demonstrated a substantial association between germline PALB2 PV/LPVs and ovarian cancer with a risk ratio of around 3 and the lifetime risk of OC estimated to be around 3–5%(Yang et al. 2020a). In our cohort, four patients were diagnosed with a high-grade serous carcinoma of the ovary or the fallopian tube and one with a borderline ovarian carcinoma. There were no cases of primary peritoneal serous carcinoma. OC was the second most prevalent malignancy in our study. Two PALB2 PV/LPV carriers in our cohort (2/61, 3.3%) were diagnosed with PaC and additional carrier with carcinoma of Papilla Vateri. Indeed there is emerging evidence that PALB2 PV/LPVs predispose patients to pancreatic cancer. It is estimated that 3–4% of patients with famillial PaC are expected to harbour PALB2 PV/LPV. In the newest version of the National Comprehensive Cancer Network (NCCN) Guidelines enhanced screening not only for BC (with possible risk reducing surgeries), but also for OC (risk reducing surgery is offered as an option) and PaC is recommended (Clinical et al. 2024). Additionally, we have identified 3 cases of malignant melanoma, 1 NET and 1 gastric cancer in our cohort, there is, however, insufficient evidence to draw a conclusion about these types of malignancies.

Double heterozygotes

The increased use of multigene panels in the recent years has led to identification of individuals harbouring more than one PV/LPV in cancer susceptibility genes, although the data is still scarce. Double heterozygous PV in BRCA1/2 are identified in 0.3% of Ashkenazi and are very rare in other populations. Lavie et al. suggest that DH PV in BRCA1/2 in females of Ashkenazi Jewish heritage does not seem to cause a more severe phenotype than in cases where only one of the genes is implicated (Lavie et al. 2011). The results of the studies on DH VP in HBOC-related genes in other populations have been conflicting and inconclusive. To the best of our knowledge no research has been conducted on DH with one of the variants being PALB2 PV/LPV. A case report by Agiannitopoulos described a female patient, who was diagnosed at the age of 42 with endometrial cancer. DH in PALB2 and MSH explained the remarkable family history of ovarian, breast, kidney and colorectal cancer and consequently the surveillance of family members was adjusted (Agiannitopoulos et al. 2020). There is emerging evidence of multiplicative effect of presence of PV/LPVs in more than one cancer susceptibility gene. Heidemann et al. showed that Caucasian female DH for BRCA1/2 seem to develop BC at a younger age and have more severe disease than carriers of a single BRCA1/2 PV/LPV (Heidemann et al. 2012). Similarly, Sokolenko et al. pointed out that the presence of additional gene defect in female BRCA1 PV carriers may further increase their chances for cancer (Sokolenko et al. 2014). We have identified three DH carriers in our PALB2 cohort with additional PV/LPVs in ATM, CHEK2, and BRCA1. The clinical presentations varied. DH patients with PV/LPVs in PALB2 and ATM or CHEK2 were diagnosed with BC at 48 and 32 years, respectively. Patient who was found to harbour PALB2 and BRCA1 PV/LPV was diagnosed with 4 malignancies: two BC, OC and PaC, supporting the multiplying effect of DH. Genetic counselling for DH carriers is complex and further studies are required to elucidate its biological effect.

Strengths and limitations of our study

There are several limitations of our study. The expected population burden of PALB2 PV/LPVs in the Slovenian population is 0.13% (Kotnik et al. 2023). The absolute number of included PV/LPV carriers was small (61). 43 (70.5%) had a cancer diagnosis. However, our cohort represents 2% of the expected population of PALB2 PV/LPV carriers in Slovenia. Also, in comparison to the literature, where mostly case series are described, this is a large cohort of PALB2 PV/LPV carriers. The subgroups of patients with different PV/LPV were very small, therefore we were not able to analyse them separately. The retrospective collection of data is always unfavourable, since data can be missing or inappropriately understood, however as it can be seen from our data, the information regarding patients’ and tumours’ characteristics was complete for patients in our study.

Its strength lies in a reliable family history, with information obtained from the Slovenian National Cancer Registry. It is one of the oldest Registries in Europe, where the diagnoses are cross-checked with histopathological reports.

In cases of rare genetic diseases large multicentric studies are required to achieve a substantial number of patients and we hope these will be able to benefit from our cohort of PALB2 PV/LPV carriers.

This report provides the first comprehensive insight into the genotype and phenotype of PALB2 PV/LPV carriers in Slovenia. The frequency of PALB2 PV/LPV in Slovenia is consistent with rates reported in other countries, accounting for 0.9% of all individuals tested for PVs in HBOC-related genes. Notably, we identified two recurrent PALB2 PV/LPVs within our population, collectively encompassing nearly half of all affected families. Of particular interest is the PALB2 c.1451T > A variant, which has not been previously documented as a recurrent mutation in any population, rendering it unique to Slovenia The most common malignancy in our cohort was as expected BC, followed by OC and PaC, which adds to the existing evidence of PALB2 involvement in the pathogenesis of thesecancer types. Despite the rarity of PALB2 carriers, who also carry PV/LPVs in other HBOC-related genes, we have identified three such individuals, and studying their disease characteristic can help elucidate the biological effect of being a DH. Overall, the results of our study provide valuable genotype and phenotype data from PALB2 positive patients which may already be utilized in a population specific assessment.

Funding

The study was supported by the Slovenian Research Agency, program number P3-0289.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Conceptualization: Vita Andreja Mesarič, Mateja Krajc, Methodology: Mateja Krajc, Kristina Drusany Starič, Simona Hotujec; Formal analysis and investigation: Vita Dragoš Šetrajčič, Petra Škerl, Srdjan Novaković, Vida Stegel; Writing - original draft preparation: Vita Andreja Mesarič; Writing - review and editing: Mateja Krajc, Ana Blatnik, Ksenija Strojnik, Kristina Drusany Starič. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval

All participants provided written informed consent. The present study was approved by the National Ethics Committee and the Institutional Ethics Committee of the Institute of Oncology Ljubljana (0120-591/2020/3 on the 20^th of January 2021). Research was conducted according to the 1975 Helsinki Declaration as revised in 1983 and the procedures used met the ethical standards of these bodies.

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No competing interests reported.

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You are reading this latest preprint version

Two recurrent pathogenic/likely pathogenic variants in PALB2 account for almost half of PALB2 positive families in Slovenia

Status:

Version 1

Abstract

Figures

Background

Methods

Patients

DNA Extraction

Next Generation Sequencing

Statistical Analysis

Results

Study cohort

PV/LPV detection rate among 4610 tested probands/families

PALB2 study cohort

Spectrum of PALB2 PV/LPVs in the Slovenian cohort of 41 PALB2 positive families

Male carriers with cancer

Clinical Characteristics of double heterozygotes

Multiple primary cancers

PALB2 positive carriers without cancer diagnosis

Discussion

Detection rate and spectrum of PALB2 PV/LPVs

Recurrent PV/LPVs in PALB2 in the Slovenian population

Malignancies among PALB2 PV/LPV carriers

Double heterozygotes

Strengths and limitations of our study

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1