Germline rad 50 mutation in a case with synchronous breast and kidney cancer: a rare case
Egyptian Journal of Medical Human Genetics volume 24, Article number: 81 (2023)
Breast cancer has been reported to occur synchronous with ovarian, endometrial and even colon cancers. A synchronous renal cancer is rare. And its association with RAD 50 mutation is not known.
We are reporting a 42 year old lady who was evaluated for a breast lump and was incidentally found to have a renal lesion. She underwent surgery for both and was found to have a T1c breast tumour and a renal cell carcinoma-clear cell variant. She was advised germline testing with next generation sequencing and multiplex ligation—dependent probe amplification due to synchronous tumours and age at diagnosis. It revealed a likely pathogenic variant in the RAD 50 gene.
The RAD 50 gene is part of the MRN complex (Mre11, Rad50 and Nbs1 also known as nibrin), which is essential for DNA repair. The recommendations for follow-up and screening are not clear for patients with a pathogenic variant of the gene. This case is presented for its rarity.
Breast cancer has been reported to occur synchronous with ovarian, endometrial and even colon cancers . But a synchronous breast and renal cancer with a likely pathogenic variant in the RAD 50 gene has not been reported so far. We are writing to highlight the possibility of this combination and to discuss the challenges we faced, with this case.
A 42 year old lady presented with the complaints of lump in the right breast of 1 month duration. She was found to have a grade 2–3, Invasive carcinoma, Not otherwise specified, with Oestrogen and progesterone receptor positivity. A PET CT scan was done as a routine staging procedure when an incidental renal mass was detected.
She underwent breast conservation surgery with sentinel lymph node biopsy and a partial nephrectomy. Histopathologic examination revealed a T1c breast tumour with negative sentinel nodes and a renal cell carcinoma, clear cell variant. She received adjuvant chemotherapy with four cycles of Taxol and Cyclophosphamide and adjuvant radiotherapy to the right breast.
In view of her age at diagnosis and synchronous malignancies, she was referred to the hereditary cancer clinic. Her family history was not significant. There was one second degree relative with breast cancer and a third degree relative with ovarian cancer (Fig. 1).
She was advised to undergo germline testing to detect the genetic mutations associated with hereditary cancers. An NGS (Next generation sequencing) and an MLPA (multiplex ligation—dependent probe amplification) was performed on the blood sample of the patient. This included a multi gene panel testing looking for high and moderate penetrance genes associated with hereditary breast and ovarian cancers.
A heterozygous likely pathogenic variant (c.2156_2157insA; p.Asp387His) wasidentified in the exon 13 of RAD50 gene in NGS. This mutation in our patient, in the RAD 50 gene, namely the single base pair insertion in the exon 13, has been reported to result in frameshift and premature truncation of the protein 5 amino acids, downstream to codon 723 (Fig. 2).
This has been found to be associated with breast and ovarian cancer patients. The association with renal cancers has not been reported.
She was advised high risk screening for breast and ovarian cancers. As this is reported to be a low penetrance gene, prophylactic surgeries were not advised.
RAD 50 gene codes for a protein which forms a complex with MrE11 and Nbs1 (MRN complex). The protein complex binds to thee DNA and plays a major part in non-homologous end joining repair. Homologous loss of this gene is associated with Nijmegen breakage syndrome like disorder . The MRN complex functions upstream of the ATM signalling. It senses DNA DSB (Deoxy ribo nucleic acid double strand break). The Mre 11 protein binds to thee DNA. Nbs 1 recruits activated ATM to the damaged sites. The interactions of Mre11 with RAD 50 provide the energy source for the MRN complex .
RAD 50 is considered to be a low penetrance gene with a relative risk less than 1.5, in the development of hereditary breast cancers . These breast cancers have reported to have poorer outcomes when compared with their normal counterparts. No clinic pathological character of these breast cancers has been reported so far . The other cancers that have been reported to manifest in association with the RAD 50 gene mutation are the ovarian, oesophageal and stomach cancers .
Hereditary renal cell cancers have been reported as a part of about 10 syndromes . DSB repair pathways have also been implicated in them. Defects in the MRN complex has been reported to cause renal cancers . The possible explanation that defects in the DSB repair pathways contribute to the development of cancers is most likely. Due to the paucity of data, we advised high risk screening for the patient and cascade testing for the first degree relatives.
RAD 50 mutation related breast cancers are rare. More so are the synchronous renal cell carcinomas. We are writing to report the rarity and to emphasise the need for improved genetic testing and serial follow-up of these patients to better understand the patient outcome and to tailor the treatment as required.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
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Ilangovan, B., Raman, G. & Mahajan, V. Germline rad 50 mutation in a case with synchronous breast and kidney cancer: a rare case. Egypt J Med Hum Genet 24, 81 (2023). https://doi.org/10.1186/s43042-023-00461-7