Circulating tumor DNA (ctDNA) is released from cancer cells and oncogenic mutations in ctDNA can be measured from plasma samples. Droplet digital PCR (ddPCR) is a sensitive and specific method for ...the detection of mutations in ctDNA. We analyzed serial plasma samples (n = 80) from ten metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor. The patients were undergoing oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan. Baseline ddPCR KRAS mutation allele frequency (MAF) values ranged from 0% to 63%. The first radiologic response evaluation criteria in solid tumors (RECIST) evaluation was performed 45-63 days after the initiation of treatment, and by this time three patients had an undetectable level of KRAS mutation, one had a MAF value of 0.5%, and one had a MAF value of 3% that had been reduced by 95% from the baseline value. In three of these patients the RECIST assessment was stable disease and in two partial response. In seven patients, ddPCR MAF values increased before radiological disease progression or death, while one patient remained disease-free with an undetectable KRAS mutation level. Next, we analyzed all available plasma samples with the Idylla ctKRAS system (n = 60), and found that the overall degree of agreement between ddPCR and Idylla was almost perfect (kappa value = 0.860). We used next-generation sequencing (NGS) to detect treatment-induced mutations in the last serial plasma sample of each patient, but were unable to find any new mutations when compared to the primary tumor. This study shows that ddPCR and Idylla are equally efficient for the detection of KRAS mutations in the liquid biopsies from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones and serve as an early sign of disease progression.
Albert de la Chapelle (1933-2020) Kääriäinen, Helena; Aittomäki, Kristiina
European journal of human genetics : EJHG,
03/2021, Letnik:
29, Številka:
7
Journal Article
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset ...multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the
fumarate hydratase
(
FH
) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for
FH
mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a
FH
mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10–20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts of families.
Surrogacy is a highly debated method mainly used for treating women with infertility caused by uterine factors. This systematic review summarizes current levels of knowledge of the obstetric, medical ...and psychological outcomes for the surrogate mothers, the intended parents and children born as a result of surrogacy.
PubMed, Cochrane and Embase databases up to February 2015 were searched. Cohort studies and case series were included. Original studies published in English and the Scandinavian languages were included. In case of double publications, the latest study was included. Abstracts only and case reports were excluded. Studies with a control group and case series (more than three cases) were included. Cohort studies, but not case series, were assessed for methodological quality, in terms of risk of bias. We examined a variety of main outcomes for the surrogate mothers, children and intended mothers, including obstetric outcome, relationship between surrogate mother and intended couple, surrogate's experiences after relinquishing the child, preterm birth, low birthweight, birth defects, perinatal mortality, child psychological development, parent-child relationship, and disclosure to the child.
The search returned 1795 articles of which 55 met the inclusion criteria. The medical outcome for the children was satisfactory and comparable to previous results for children conceived after fresh IVF and oocyte donation. The rate of multiple pregnancies was 2.6-75.0%. Preterm birth rate in singletons varied between 0 and 11.5% and low birthweight occurred in between 0 and 11.1% of cases. At the age of 10 years there were no major psychological differences between children born after surrogacy and children born after other types of assisted reproductive technology (ART) or after natural conception. The obstetric outcomes for the surrogate mothers were mainly reported from case series. Hypertensive disorders in pregnancy were reported in between 3.2 and 10% of cases and placenta praevia/placental abruption in 4.9%. Cases with hysterectomies have also been reported. Most surrogate mothers scored within the normal range on personality tests. Most psychosocial variables were satisfactory, although difficulties related to handing over the child did occur. The psychological well-being of children whose mother had been a surrogate mother between 5 and 15 years earlier was found to be good. No major differences in psychological state were found between intended mothers, mothers who conceived after other types of ART and mothers whose pregnancies were the result of natural conception.
Most studies reporting on surrogacy have serious methodological limitations. According to these studies, most surrogacy arrangements are successfully implemented and most surrogate mothers are well-motivated and have little difficulty separating from the children born as a result of the arrangement. The perinatal outcome of the children is comparable to standard IVF and oocyte donation and there is no evidence of harm to the children born as a result of surrogacy. However, these conclusions should be interpreted with caution. To date, there are no studies on children born after cross-border surrogacy or growing up with gay fathers.
Significance The major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing of 24 high-risk familial BRCA1/2 -negative ...breast cancer patients and further genotyping of a large sample set of breast/ovarian cancer cases and controls was used to discover previously unidentified susceptibility alleles and genes. A significant association of a FANCM nonsense mutation with breast cancer, especially triple-negative breast cancer, identifies FANCM as a breast cancer susceptibility gene. Identification of such risk alleles is expected to improve cancer risk assessment for breast cancer patients and families, and may lead to improvements in the prevention, early diagnosis, and treatment of cancer.
Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1 , BRCA2 , PALB2 , CHEK2 , and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M ( FANCM ), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls odds ratio (OR) = 1.86, 95% CI = 1.26–2.75; P = 0.0018, with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81–6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.
Purpose: HuR is an mRNA-binding protein that enhances the stability of certain transcripts and can regulate their translation. Elevated
cytoplasmic expression of HuR protein has been linked to ...carcinogenesis and is associated with reduced survival in breast,
ovarian, and gastric adenocarcinomas.
Experimental Design: Here, we have explored the relevance of HuR in familial breast cancer. Tumor samples were collected from patients with identified
BRCA1 ( n = 51) or BRCA2 ( n = 47) mutations or familial non- BRCA1/2 cases ( n = 525), and analyzed by immunohistochemistry.
Results: Among familial non- BRCA1/2 breast cancer patients, cytoplasmic HuR protein expression was present in 39.4% of the cases and was associated with estrogen
receptor negativity, progesterone receptor negativity, p53 positivity, high tumor grade, and ductal type of the tumor. In
multivariate analysis, cytoplasmic HuR expression was an independent marker of reduced survival in the non- BRCA1/2 group along with tumor size >2 cm, lymph node metastasis, and high histologic grade. In patients with BRCA1 or BRCA2 mutations, cytoplasmic HuR expression was more frequent (62.7% for BRCA1 and 61.7% for BRCA2 ) than in the non- BRCA1/2 group, but in BRCA -mutated subgroups cytoplasmic HuR expression did not associate with survival.
Conclusions: Our results show that HuR is an important prognostic factor in familial breast cancer patients and may contribute to carcinogenesis
in this disease.
Purpose: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival.
Experimental Design: We defined the PALB2 mutation status in 947 ...familial and 1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor
characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases.
Results: The PALB2 1592delT mutation was found in 19 familial 2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001 and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype
more often (54.5%; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancer patients. They were also more often of higher
grade ( P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 ( P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24;
P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up ( P = 0.04).
Conclusions: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest
a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.
Abstract
The risk of breast cancer associated with
CHEK2:
c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in ...combination with
CHEK2
:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify
CHEK2
:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in
CHEK2
:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline
CHEK2
:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous
CHEK2
:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in
CHEK2
:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a
CHEK2
:c.1100delC-specific genetic modifier. Further studies of
CHEK2
:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman's life. Despite intense research, no major genes ...have been found to explain the complex genetic etiology.
We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA.
We have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.
Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC). The role of ...other breast cancer genes in MBC is less well understood.
In this study, we have genotyped 68 MBC patients for the known breast or ovarian cancer associated mutations in the Finnish population in CHEK2, PALB2, RAD51C, RAD51D, and FANCM genes.
CHEK2 c.1100delC mutation was found in 4 patients (5.9%), which is significantly more frequent than in the control population (OR: 4.47, 95% CI 1.51-13.18, p = 0.019). Four CHEK2 I157T variants were also detected, but the frequency did not significantly differ from population controls (p = 0.781). No RAD51C, RAD51D, PALB2, or FANCM mutations were found.
These data suggest that the CHEK2 c.1100delC mutation is associated with an increased risk for MBC in the Finnish population.
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