Rare germline chromosome 1 duplication identified in young male with colon cancer: a case report investigating causality
Highlight box
Key findings
• Our findings refute that a duplication covering TTF2, MIR942, and TRIM45 on chromosome 1 is a monogenetic cause of colorectal cancer (CRC).
What is known and what is new?
• Monogenetic germline variants are known to cause early onset CRC, and disruption of the Wnt signaling pathway is proven causative in e.g., patients with familial adenomatous polyposis (caused by pathogenic variants in the APC gene).
• Our findings do not support that a duplication including the MIR942-gene (operating within the Wnt signaling pathway) is a monogenetic cause of CRC in a 24-year-old male.
What is the implication, and what should change now?
• Further studies should investigate whether this duplication is a risk factor for CRC in combination with other genetic- and non-genetic risk factors for CRC, or whether it is an incidental finding.
Introduction
Colorectal cancer (CRC) is the third most common cancer in both males and females (1). The occurrence is highest in patients older than 50 years of age. While the occurrence and mortality have decreased for patients older than 50 years—largely due to screening programs which have proven to reduce mortality (2-4), the occurrence among young adults (particularly those <40 years at diagnosis) have increased (5). Twin studies have shown that the heritable component in CRC is estimated to be up to 35% (6). While polygenic risk scores (PRS) have proven to be useful in estimating individual risk among patients with no family history of CRC (7,8), their use in a clinical setting has not yet been implemented.
In the following letter, we present a case of a 24-year-old man who developed colonic cancer and carries a rare duplication on chromosome 1 previously identified in a family also burdened by CRC and considered a likely cause of disease (9). We present this case in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-148/rc).
Case presentation
A 24-year-old male was admitted to the hospital with one month’s history of abdominal pain, bloating, nausea, vomiting, and obstipation. The patient’s medical history was otherwise uneventful. Blood work came back with increased levels of hemoglobin, leucocytes, neutrophils and C-reactive protein (CRP). Upon admission the patient was suspected of having inflammatory bowel disease, coeliac disease, or an infection, however, all additional tests came back negative. Fecal culturing, however, revealed growth of clostridium difficile. A subsequent computed tomography (CT) scan revealed a pre-stenotic dilatation of the terminal ileum and unspecific hepatic changes, suggested by the radiologist to be cysts or hemangiomas. The patient underwent a diagnostic laparoscopy revealing a tumor located in the lateral cecal wall. In addition, the laparoscopy showed two peritoneal white elements highly suspect of being metastases. Histopathologic characterization of the tumor showed that the tumor was an adenocarcinoma with a pathogenic variant in KRAS [p.(Gly12Asp)]. Immunohistochemistry analysis (including expression of MMR proteins) and somatic genetic testing came back without other pathogenic findings. A magnetic resonance imaging (MRI) scan determined the hepatic changes were in fact metastases and peritoneal carcinosis. Subsequently, the patient was referred to oncological treatment. Even though the patient had disseminated disease the initial treatment had a curative aim with neoadjuvant chemotherapeutic treatment to allow for surgical removal. The patient was treated with fluorouracil, calcium folinate, and irinotecan, but after 8 weeks of treatment blood work revealed increased levels of carcinoembryonic antigen (CEA). A follow-up CT scan showed disease progression resulting in a change of treatment adding bevacizumab and oxaliplatin to the chemotherapeutic treatment. Follow-up scans showed regression of the metastases and the primary tumor, but the patient’s treatment was complicated by numerous episodes of sub-ileus and ileus. A novel ileostomy was placed to alleviate the pain, however, during this procedure, carcinosis was observed in all four quadrants. After 6 months of treatment, no substantial regression was obtained, and the patient and his family were informed that further treatment would be palliative. Seven months after the initial diagnosis the patient died.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the index patient’s family for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.
Genetics
In parallel with the patient’s treatment, he was referred for genetic counselling. This included mapping of the family pedigree (Figure 1A) and germline genetic testing. An in-house gene panel consisting of 17 CRC/polyposis predisposing genes was analyzed. The gene panel included the following genes: APC, AXIN2, BMPR1A, EPCAM, GREM1, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, PTEN, SMAD4, and STK11. No pathogenic variants were identified. Thus, a mosaic screening of variants in APC and additional germline genetic testing of variants in BRCA1, BRCA2, BRIP1, CDH1, PALB2, PTEN, RAD51C, RAD51D, and TP53 was initiated. This did not reveal any pathogenic genetic variants either, resulting in risk assessment for the patient’s first-degree relatives based on the family pedigree.
A few months after the patient died, his mother and sister were referred for genetic counselling. They had not accompanied the patient when he underwent genetic testing and wanted to know their risk of developing CRC. The family was offered whole genome sequencing (WGS) using DNA from the patient. WGS revealed that the patient carried a duplication on chromosome 1 [Chr1(hg19):g.117487504_117687735dup]. The duplication was classified as a variant of unknown significance (VUS, class 3). The duplication on chromosome 1 spans a region of 200 kb and covers the genes CD101, TTF2, MIR942, TRIM45, and parts of the genes PTGFRN and VTCN1, and was shown to be located in tandem (Figure 1B,1C). The duplication had not previously been described in gnomAD or in the literature. However, a similar duplication covering an overlapping area (including TTF2, MIR942, and TRIM45) had previously been reported in another family with CRC and was considered a likely cause of CRC in the family (9). Segregation analysis revealed that the duplication was maternally inherited. On the maternal side of the family, there had been one case of a tubular adenoma with high-grade neoplasia at 71 years of age in the patient’s maternal grandmother and one case of CRC at 67 years of age in her mother (the patient’s great-grandmother). The patient’s maternal grandfather had a tubular adenoma with low-grade neoplasia at 75 years of age (and his father had chronic myeloid leukemia at 75 years of age). This led to genetic testing of the patient’s maternal grandparents. The duplication proved to be inherited from the patient’s maternal grandfather, who had never had CRC or the removal of polyps with high-grade neoplasia.
Moreover, gene panel analysis identified 11 variants (Table 1) in the patient using a gene panel of 390 known and suspected cancer predisposing genes and an allele frequency ≤1%. The most interesting variant in relation to CRC was a relatively rare synonymous MSH2 variant [c.843A>T, p.(Ser281=)] and a rare missense variant in CHEK2 [c.1522C>G, p.(Leu508Val)]. The MSH2 variant is reported 6 times in gnomAD (v.2.1.1) in heterozygote form. In silico analysis indicates that it has no effect on splicing. Moreover, the variant is reported 11 times in the ClinVar database as likely benign (variation ID: 237412). Interestingly, the variant was identified in homozygous form in our patient. However, based on the current knowledge we also classify the variant as likely benign. The variant in CHEK2 is reported 3 times in gnomAD v.2.1.1 in the European (non-Finnish) population. The variant changes a weakly conserved amino acid, and in silico analysis accordingly indicates that the variant was unlikely to be pathogenic. Functional analysis showed that the variant had an intermediate effect in a CHEK2 activity assay but behaved as wild-type in a KAP1 activity assay (10). Based on these data the variant was classified as a VUS. The nine other variants are regarded as being too common based on allele frequency or not relevant for CRC. We were unable to examine for de novo variants, as the parents only agreed to data analysis of the chromosome 1 duplication. Subsequently, we calculated PRS for CRC in our patient using 95 single nucleotide polymorphisms (SNPs) correlated to the risk of CRC. The methodology employed is described in detail elsewhere (11). The calculated PRS for our patient was 7.87, indicating an average risk of developing CRC compared to other individuals with CRC. This suggests that our proband’s risk of CRC, based on the PRS score, falls within the typical range, neither being particularly elevated nor reduced.
Table 1
Chromosome: position | Reference/alteration | Variant allele frequency | Gene | HGVS c. (clinically relevant) | HGVS p. (clinically relevant) | GnomAD v.2.1.1. (for non-Finnish Europeans) [N] |
---|---|---|---|---|---|---|
8:30948045 | A/G | 0.785714 | WRN | NM_000553.6: c.1717A>G | NP_000544.2: p.(Thr573Ala) | 0.19186% [247] |
11:1263400 | A/G | 0.481481 | MUC5B | NM_002458.3: c.5290A>G | NP_002449.2: p.(Arg1764Gly) | 0.080569% [103] |
2:47641458 | A/T | 1.0 | MSH2 | NM_000251.3: c.843A>T | NP_000242.1: p.(Ser281=) | 0.0046643% [6] |
1:235894366 | A/C | 0.411765 | LYST | NM_000081.4: c.8913T>G | NP_000072.2: p.(Asn2971Lys) | 0.44919% [580] |
1:235875386 | T/C | 0.384615 | LYST | NM_000081.4: c.9896A>G | NP_000072.2: p.(Tyr3299Cys) | 0.019941% [16] |
7:148524327 | A/G | 0.468085 | EZH2 | NM_004456.5: c.657T>C | NP_004447.2: p.(Pro219=) | 0.075923% [98] |
10:50732202 | T/G | 0.318182 | ERCC6 | NM_000124.4: c.1274A>C | NP_000115.1: p.(Asp425Ala) | 0.29267% [371] |
11:71146886 | C/G | 0.45283 | DHCR7 | NM_001360.3: c.964-1G>C | p. (?) | 0.60784% [722] |
22:29085143 | G/C | 0.404255 | CHEK2 | NM_007194.4: c.1522C>G | NP_009125.1: p.(Leu508Val) | 0.0027606% [3] |
13:103498672 | C/T | 0.479167 | ERCC5 | NM_000123.4: c.56C>T | NP_000114.3: p.(Pro19Leu) | 0.10878% [139] |
17:63554469 | G/A | 0.418182 | AXIN2 | NM_004655.4: c.270C>T | NP_004646.3: p.(Asp90=) | 0.12314% [159] |
HGVS, Human Genome Variation Society; c., nucleotide change; p., amino acid change.
Discussion
Genetic predisposition to CRC is well-known with Lynch syndrome and familial adenomatous polyposis, most commonly caused by pathogenic variants in the mismatch repair genes or by deletions in EPCAM and the APC gene respectively (12). In recent years more genes have been linked to an increased risk of developing CRC (with or without polyposis)—among them are MLH3, MSH3, MUTYH, GREM1, POLE, POLD1, RNF43, RPS20 and NTHL1 (12). Furthermore, a combination of common genetic variants and a family history of CRC, can be used in the calculation of a PRS that can predict an individual’s risk of CRC (13). Additionally, copy number variations (CNV) of genes relevant for CRC have been proven to increase the risk of CRC, e.g., duplications in GREM1 (14) and deletions in EPCAM (15). In this case, we did not identify any pathogenic variants in well-established CRC-associated genes, nor did we find a particularly high PRS. We did, however, identify a duplication on chromosome 1. The duplication identified in our patient overlaps with a duplication previously identified in two brothers who developed CRC at the ages of 52 and 61, respectively (9). Both duplications covered the TTF2, MIR942, and TRIM45 genes. Franch-Expósito et al. performed whole exome sequencing (WES) in 71 patients from 38 families with a family history of CRC. WES data was analyzed for variants in known CRC causative genes, and subsequently assessed for CNVs if no germline single nucleotide variants (SNV) were found. After identifying the duplication on chromosome 1 they performed an expression analysis on RNA from blood which showed an upregulation of the TTF2 transcript which was not found in controls, while no significant change was observed for TRIM45. This finding was confirmed by the authors through a real-time quantitative polymerase chain reaction (PCR) analysis, and tumor gene expression analysis found that MIR942 also proved upregulated (9). It is worth mentioning that the duplication did not segregate fully in the family described by Franch-Expósito et al. as the two brother’s mother (CRC 84 years old) did not carry the variant. However, the risk of CRC increases with increasing age—so the mother’s CRC is not necessarily suspected of being attributed to a genetic predisposition. MIR942 has been found to be involved in the regulation of the Wnt signaling pathway, which will lead to CRC development when it is disrupted (16-18). These studies were the reason for investigating the duplication further when identified in our patient. However, as the duplication did not segregate with CRC in our family, we cannot say that our findings support pathogenicity. Whether the duplication could play a role if occurring alongside other genetic and non-genetic risk factors is still unknown, although the PRS calculated for our patient did not put him at an increased risk of CRC.
Conclusions
We did not identify a monogenetic cause of the early onset and aggressive CRC in our patient. Further studies are needed to elucidate whether the duplication on chromosome 1 may play a role in CRC risk either alone or in combination with other risk factors.
Acknowledgments
We would like to thank the family presented in this case for their agreement to publish the findings of their genetic counselling and testing.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-148/rc
Peer Review File: Available at available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-148/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-148/coif). K.W. reports a speaking engagement at Seagen Denmark ApS for which she received payment. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the index patient’s family for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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