Preimplantation genetic diagnosis for hereditary cancer syndrome: local experience

Abstract

A 33-year-old woman was referred for consideration of PGD because she was a BRCA2 gene mutation carrier. She had cancer of the right breast at the age of 24 years and underwent modified radical mastectomy with axillary dissection and immediate latissimus dorsi flap reconstruction. Adjuvant chemoradiotherapy was given and she was prescribed tamoxifen for 5 years after the operation. Her paternal grandmother had breast cancer diagnosed at the age of 60 years. Genetic screening was performed and confirmed the patient to be a BRCA2 mutation carrier. Her elder brother and her father underwent the spot test and were found to carry a BRCA2 mutation but her younger sister was not affected. Laparoscopic ovarian cystectomy was performed for a hyperechoic cyst noted over the right ovary, which was confirmed to be an endometriotic cyst. After a multidisciplinary meeting of clinical geneticists, breast surgeons, oncologists, gynaecologists, psychologists, nurses, and academics in the ethics department, followed by psychological assessment and also counselling, she was offered in-vitro fertilisation (IVF) and PGD. Her IVF and PGD cycle was performed in 2011, using an antagonist protocol with letrozole co-treatment. Fifteen oocytes were retrieved and 12 were fertilised following intracytoplasmic sperm injection (ICSI). Blastomere biopsy was performed on eight goodquality cleaving embryos and five were confirmed to be free of the BRCA2 mutation. Two unaffected blastocysts were transferred, resulting in a singleton pregnancy and one unaffected blastocyst was cryopreserved. She delivered a baby boy at term by caesarean section. Postnatal cord blood confirmed that the baby boy did not carry the BRCA2 mutation. Case 2A 33-year-old woman was referred for PGD because she was a carrier of FAP truncating germline mutation APC c.532-8G>A (NG_008481:g93262G>A) with a strong family history of colonic cancer. She underwent colonoscopy surveillance and more than 100 small colonic polyps were found. She was advised to have a prophylactic colectomy but was firm in her request to get pregnant with PGD treatment before the definitive treatment while fully understanding the risks of malignancy because of the delay in definitive treatment. She underwent an IVF cycle in 2012. Of 19 oocytes retrieved, 16 underwent ICSI. Fifteen were fertilised and 15 embryos were available for blastomere biopsy on day 3. Five embryos were found without the FAP mutation and four goodquality blastocysts were cryopreserved due to the risk of ovarian hyperstimulation syndrome. She failed to conceive in two frozen embryo transfer (FET) cycles with one blastocyst replaced in each cycle. She subsequently underwent the last FET cycle with two blastocysts transferred, and a consequent singleton pregnancy. The pregnancy is 26 weeks' gestation at the time of writing. The couple refused an invasive prenatal test and requested postnatal cord blood confirmation. Case 3A 37-year-old patient was referred from a clinical geneticist for PGD as her husband was diagnosed to have neuro...

Genetic testing and counselling

“…The technique is applicable to hereditary diseases, such as thalassaemia and haemophilia, as well as hereditary cancer syndromes, including breast and colon cancers. 4 This is usually followed by confirmation by prenatal genetic testing after pregnancy.…”

Preimplantation genetic testing for embryos predisposed to hereditary cancer: Possibilities and challenges

“…found that only one in three couples agreed to use invasive PNT with the possibility of terminating the pregnancy. 22 Similarly, a study by Derks-Smeet et al. showed that the majority of couples with hereditary breast and ovarian cancer (HBOC) pathogenic variants refused to undergo PNT and even refused to follow natural conception.…”

“… 13 HBOC Autosomal dominant BRCA2 ; BRCA1 gene pathogenic variant C.7436_7805del [GenBank U43746]); BRCA1 pathogenic variant carrier (5273G[A In exon 19) Breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer Lee et al. 22 and Ramón et al. 27 FAP Autosomal dominant Truncating germline pathogenic variants in the APC gene APC gene, C.532-8G > A (NG_008481:G93262g > A); an AGTT deletion pathogenic variant in exon 15 of the APC gene FAP is hundreds or even thousands of polyps growing in the gastrointestinal tract, primarily in the colon Lee et al.…”

“… 27 FAP Autosomal dominant Truncating germline pathogenic variants in the APC gene APC gene, C.532-8G > A (NG_008481:G93262g > A); an AGTT deletion pathogenic variant in exon 15 of the APC gene FAP is hundreds or even thousands of polyps growing in the gastrointestinal tract, primarily in the colon Lee et al. 22 and Davis et al. 28 RB1 Autosomal dominant Caused by pathogenic variants in the RB1 gene Single base pair substitution at the 5′ end of intron 12 (splice site pathogenic variant) of the RB gene (1353 + 1G→A).…”

“…NF1 c.4495C > T (NM_000267) Young patient with typical neurofibromatosis type 1 diagnosed with a unilateral vestibular schwannoma Lee et al. 22 and Huq et al. 33 APC : Adenomatous polyposis coli; CNS: Central nervous system; CRC: Colorectal cancer; FAP: Familial adenomatous polyposis; HBOC: Hereditary breast and ovarian cancer; HNPCC: Hereditary nonpolyposis colorectal cancer; LFS: Li-Fraumeni syndrome; LS: Lynch syndrome; MEN1: Multiple endocrine neoplasia type 1; MEN2: Multiple endocrine neoplasia type 2; MMR: Mismatch repair; MTC: Medullary thyroid cancer; NF1: Neurofibromatosis type 1; NF2: Neurofibromatosis type 2; RB1: Retinoblastoma; RET: Rearranged during transfection.…”