You are currently viewing a new version of our website. To view the old version click .
MDPIMDPI
Search all articles
Cancers
Download PDF
  • Article
  • Open Access

11 January 2024

Prevalence and Distribution of MUTYH Pathogenic Variants, Is There a Relation with an Increased Risk of Breast Cancer?

,
,
,
,
,
,
,
,
and
1
Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
2
Department of Medical Oncology, Clínica Universidad de Navarra, 28027 Madrid, Spain
*
Author to whom correspondence should be addressed.
Cancers2024, 16(2), 315;https://doi.org/10.3390/cancers16020315
This article belongs to the Special Issue Risk Factor Prediction, Diagnosis and Treatment of Breast Cancer
Version Notes
Order Reprints
Review Reports

Simple Summary

Colorectal cancer is often associated with MUTYH mutations, but their connection to breast cancer remains unclear. We aimed to assess if MUTYH mutations contribute to breast cancer susceptibility. Analyzing data from 3598 patients, we found MUTYH mutations in 1.6%, with a significant association in colonic polyposis cases. However, our findings did not reveal a substantial association between MUTYH mutations and breast cancer. These insights emphasize the need for cautious interpretation of MUTYH mutations in breast cancer risk assessments.

Abstract

Background: MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility. Methods: We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants. Results: Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2–2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5–3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2–22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7–2.3). Conclusion: In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.

1. Introduction

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide [1]. Pathogenic genetic mutations in genes associated with a significant or moderate cancer risk are identified in 6–10% of all CRC and even in 20% of cases diagnosed before the age of 50. Hereditary colorectal cancer syndrome is classified as non-polyposis and polyposis. The most common is hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, which accounts for about 3% of cases. In the case of hereditary polyposis colorectal cancer syndrome, the most frequent syndrome is familial adenomatous polyposis (FAP) caused by mutation in the adenomatous polyposis coli (APC) gene, which accounts for about 1% of cases. There are also other polyposis syndromes, such as MUTYH-associated polyposis (MAP), which accounts for about 0.5% of cases [2]. MAP is an autosomal recessive syndrome caused by biallelic germline mutations (either homozygous or compound heterozygous) on MUTYH that predisposes to both colonic polyposis and colorectal carcinoma [3,4].
MUTYH is a gene located in the locus 1p34.1 [5]. It encodes a DNA glycosylase of the base excision repair (BER) that prevents mutations due to oxidative DNA damage. Specifically, it targets guanine (G): cytosine (C) → thymine (T): adenosine (A) transversions mediated by guanine oxidation (8-oxoG) that mispairs with A residues instead of C. MUTYH-inherited variants can induce somatic APC mutations in colorectal tumors [6]. The two most common pathogenic/like pathogenic MUTYH mutations in the Caucasian population are p.Y179C (also known as Y151C, Y165C or Y176C) and p.G382D (also known as G368D or G393D) [7,8,9]. Although less described, these mutations are also linked to the risk of extracolonic cancers like duodenal, ovarian, bladder or skin [10].
There has been controversy about whether MUTYH mutations are associated with breast cancer. Breast cancer (BC) is the most common cancer and the fourth leading cause of cancer death worldwide [1]. Between 5% and 10% of individuals with BC have a genetic predisposition. Most cases of hereditary breast and ovarian cancer syndrome (HBOCS) are caused by germline mutations in BRCA1 or BRCA2. This syndrome is characterized by an increased risk of certain types of cancers, especially breast cancer, and an early onset of these cancers. However, this syndrome can occur without BRCA1/2 mutation due to alteration of other genes involved in DNA repair like RAD51, ATM, CHEK2 or BRIP1 [11].
The first studies that suggested the correlation between MUTYH and BC appeared in the year 2005. Nielsen et al. 2005 detected MUTYH pathogenic variations in 40 patients out of 170 patients with colonic polyposis and an absence of the APC mutation. In that group, 18% of female patients (4/22) presented with breast cancer [12]. There are many descriptive studies detecting MUTYH mutations in breast cancer patients [13]. Moreover, there is a molecular plausibility for that correlation. BRCA1 and BRCA2 are two tumor suppressor genes that participate in the repair of double-stranded DNA breaks through the homologous recombination pathway [11]. BRCA has also been linked to the repair processes of the oxidative lesion 8-oxoG, where MUTYH also performs its function [14].
However, there are case–control studies that have found no correlation between carriers of MUTYH mutations and breast cancer [15]. Several studies have examined the frequency of the two common missense mutations (p.Y179C and p.G382D), and approximately 1–2% of the general population (of European origin) is predicted to be a carrier [16]. So, it is reasonable that these variants may appear as incidental findings in germline studies.
The objective of this study is to describe the patients carrying MUTYH mutations in our center and to try to determine if there is a relationship with breast cancer. Elucidating this relationship has implications for diagnosis (need to include MUTYH in gene panels to study HBOCS), screening (need for breast imaging studies in MUTYH carriers) and patient information.

2. Materials and Methods

A retrospective study was conducted at the ‘Hereditary Cancer Unit’ of La Paz University Hospital (Madrid) from June 2018 to June 2023. The study included the adult population (>18 years old) which attended during this period. The demographic, clinical and familial histories were collected from genealogical trees and medical records. We selected patients in whom a variant was detected in MUTYH.
The indication for genetic testing in suspected hereditary syndrome was performed following the NCCN (National Comprehensive Cancer Network) guideline criteria. For the genetic study of MUTYH, DNA was extracted from peripheral blood using a magnetic separation method on the Chemagic 360 or Chemagen Magtration system 8Lx (PerkinElmer). Then, the study could be performed in two settings. If a familial genetic variant in the index case was already identified, cascade testing was conducted for at-risk relatives. This involved amplification through polymerase chain reaction (PCR), followed by sequencing of the amplified fragments using capillary electrophoresis on an ABI3730 (Applied Biosystems). If hereditary syndrome was suspected, Target Next Generation Sequencing (NGS) panel based in hybridization capture was carried out. It was performed on the MiSeq, HiSeq or NextSeq platform (Illumina) following the paired-ends strategy. Selection of target regions was performed using OncoClever-GeneSGKit capture. The bioinformatics analysis (comparison of the DNA sequence obtained with the reference genomic sequence, GRCh38) was conducted with platforms like DATA GENOMICS (IMEGEN) or SOPHIA-GENETICS (SOPHIA DDM®). If FAP was suspected, the NGS included the genes APC and MUTYH. In patients with early onset colorectal cancer, the NGS included the genes MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, POLD, MUTYH and APC. If HBOCS was suspected, the NGS included MUTYH, BRCA1, BRCA2, PTEN, CDH1, CHEK2, BLM, XRCC2, MSH2, MSH6, MLH1, FAM175A, ATM, PALB2, STK11, MEN1, BARD1, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, PMS2 and EPCAM. Any changes detected by NGS are subsequently confirmed using automatic bidirectional sequencing (Sanger). The variants were analyzed using databases such as ClinVar, HGMD Pro or LOVD. The nomenclature used was approved by the Human Genome Variation Society (HGVS). The variants were classified in accordance with the American College of Medical Genetics and Genomics (ACMG) into a five-tier system (class 5: deleterious; class 4: likely deleterious; class 3: uncertain significance; class 2: likely benign; and class 1: benign).
The prevalence of the mutations detected and patient characteristics were reported with descriptive statistics. The demographic, clinical and pathological characteristics were compared using chi-square tests for categorical variables. The odds ratio (OR) was compared between the different groups for each clinical factor using Fisher’s exact test. p values <0.05 were considered statistically significant. Statistical analysis was carried out using IBM SPSS Statistics for Windows Version 19.0 (IBM Corporation, Armonk, NY, USA).

3. Results

From June 2018 to June 2023, 3598 patients were assessed in the Hereditary Cancer Unit. The median age was 56 years old (range: 18–97), and the majority were female (n = 2690, 74.8%). In relation to the most frequent underlying pathology, 766 had breast cancer (21.3%), 399 had colorectal cancer (11.1%), 183 had ovarian cancer (5.1%), 175 had pancreatic cancer (4.9%), 150 had colonic polyposis (4.2%) and 85 had prostate cancer (2.4%). Of the 766 breast cancer patients, 13 were male (1.7%).

3.1. Characteristics of MUTYHmut Carriers

Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2–2.0). The median age was 60 years old (range: 18–85), and the majority were female (n = 44, 78.6%). In total, 36 patients were the index case (64.3%). The suspected hereditary syndrome that prompted the study were HBOCS (n = 27, 48.2%), familial polyposis (n = 18, 32.1%), HNPCC (n = 7, 12.5%), hereditary leukemia (n = 3, 5.4%) and hereditary renal cancer (n = 1, 1.8%). The underlying pathology was colonic polyposis (n = 17, 30.4%), breast cancer (n = 14, 25%), colorectal cancer (n = 7, 12.5%), ovarian cancer (n = 5, 8.9%), pancreatic cancer (n = 3, 5.4%), renal cancer (n = 3, 5.4%), prostate cancer (n = 2, 3.6%), hematological cancer (n = 2, 3.6%), melanoma (n = 2, 1.8%), endometrial cancer (n = 1, 1.8%) and lung cancer (n = 1, 1.8%). A total of 10 patients had multiple cancers (17.8%), 15 patients did not have cancer or polyposis (26.8%), and 3 patients had colonic polyps and cancer (endometrial, ovarian and colorectal). Patient characteristics are summarized in Table 1.
Table 1. Baseline characteristics. HBOCS = hereditary breast and ovarian cancer syndrome; HNPCC = hereditary non-polyposis colorectal cancer.

3.2. Genetic Findings of MUTYHmut Carriers

The most frequent mutations were p.G382D/Class 5 (n = 39, 62.9%), p.Y179C/Class 5 (n = 6, 9.7%), p.E410Gfs*43/Class 5 (n = 3, 4.8%), p.R368Qfs*164/Class 4 (n = 3, 4.8%), p.Q338*/Class 5 (n = 2, 3.2%), p.R97Q/Class 3 (n = 1, 1.6%), p.R109W/Class 4 (n = 1, 1.6%), p.E453del/Class 5 (n = 1, 1.6%), p.D147H/Class 3 (n = 1, 1.6%), p.Q324=/Class 1 (n = 1, 1.6%), p.R426C/Class 3 (n = 1, 1.6%), c.933+3A>C/Class 3 (n = 1, 1.6%), c.934-2A>G/Class 4 (n = 1, 1.6%) and c.997+1G>T/Class 4 (n = 1, 1.6%). The majority were heterozygous (n = 50, 89.2%). Two patients were p.G382D homozygous (one patient with colonic polyps and another with sister with colonic polyps). Four patients were compound heterozygous: p.G382D + p.R97Q (one patient with breast cancer), p.G382D + p.R109W (one patient with colonic polyps), p.G382D + p.E453del (one patient with endometrial cancer), and p.Y179C + p.E410Gfs*43 (one patient with nonpolyposis colorectal cancer).
In five patients, there was a pathogenic/likely pathogenic mutation in another gene: RAD50 p.E723Gfs*5/Class 5 (one patient with breast cancer), RAD50 p.E723Gfs*5/Class 5 (one patient with nonpolyposis colorectal cancer), APC p.N1739fs/Class 5 (one patient with polyposis), NF1 p.N2220Ifs*25/Class 5 (one patient with family history of breast cancer) and SDHB p.P56Yfs*5/Class 5 (one patient with renal cancer). In another four patients, there was a variant of uncertain significance: APC p.D1711V/Class 3 (one patient with polyposis), BRCA2 p.E170A/Class 3 (one patient with breast cancer and nonpolyposis colorectal cancer), BRCA2 Class 3 (one patient with ovarian cancer) and ATM c.720T>C/Class3 (one patient with breast cancer).
Genetic results are summarized in Table 2. Table 3 summarizes the phenotype mutation in MUTYH and the presence of other mutations in other genes for each patient.
Table 2. Genetic results.
Table 3. Summary of patients with MUTYH mutations. The classification of the mutation according to ACMG is indicated in parenthesis. HBOCS = hereditary breast and ovarian cancer syndrome, HNPCC = hereditary non-polyposis colorectal cancer, HL = hereditary leukemia, HRC = hereditary renal cancer, Y = yes, N = no, BC = breast cancer, OC = ovarian cancer, PCC = pancreatic cancer, PC = prostate cancer, CRC = colorectal cancer, RC = renal cancer, EC = endometrial cancer, LC = lung cancer, L = leukemia, M = melanoma.

3.3. Breast Cancer in MUTYHmut Carriers

In relation to patients with breast cancer with MUTYH mutations (n = 14). The median age was 51.5 years old (range: 33–78), and all were females. The majority were ductal (n = 11, 78.6%), histological grade 2 (n = 7, 50%) and stage I-II (n = 10. 71.4%). The molecular subtypes were luminal A (n = 5, 35.7%), luminal B (n = 5, 35.7%) and triple negative (n = 4, 28.6%). The MUTYH mutations found were p.G382D (n = 7, one compound heterozygous with p.R97Q), p.Y179C (n = 2, one with ATM mutation), p.Q338* (n = 2), p.E410Gfs*43 (n = 1, with BRCA2 mutation), c.933+3A>C (n = 1) and c.934-2A>G (n = 1). In four patients with polyposis and without breast cancer, there was a family history of breast cancer.

3.4. Prevalence of MUTYH Mutations and Association with Pathologies

The prevalence of MUTYH mutations was 1.6% (95%CI: 1.2–2.0) in our setting, 11.3% (95%CI: 6.3–16.4) in colonic polyposis, 1.7% (95%CI: 0.0–3.6) in pancreatic cancer, 2.7% (95%CI: 0.4–5.0) in ovarian cancer, 2.4% (2/85, 95%CI 0.0–5.6) in prostate cancer, 1.8% (95%CI: 0.9–2.8) in breast cancer and 1.8% (95%CI: 0.5–3.0) in colorectal cancer. The prevalence of MUTYH mutation was significantly higher in the subpopulation with polyposis vs. without (11.3% vs. 1.1%, p < 0.00001) and was not significantly different in the subpopulation with colorectal cancer vs. without (1.8% vs. 1.6%, p = 0.74) or breast cancer vs. without (1.8% vs. 1.5%, p = 0.49). The odds ratio (OR) for the presence of MUTYH mutation was only significant in colonic polyposis (OR = 11.2, 95%CI: 6.2–22.3). It was not significant in the case of ovarian cancer (OR = 1.8, 95%CI: 0.7–4.7), prostate cancer (OR = 1.5, 95%CI: 0.4–6.4), breast cancer (OR = 1.2, 95%CI: 0.7–2.3), colorectal cancer (OR = 1.1, 95%CI: 0.5–2.6) or pancreatic cancer (OR = 1.1, 95%CI: 0.3–3.6). The results are summarized in Table 4.
Table 4. Prevalence and odds ratio (OR) of MUTYH mutations in general population and across different types of tumors.

4. Discussion

It is necessary to know the characteristics of MUTYH carriers in order to provide the best prognostic information to our patients. The results of our study indicate that the prevalence of germline alterations in MUTYH in our series is 1.6%, and among breast cancer patients, it is 1.8%. A statistically significant association was detected between MUTYH carriers and the presence of colonic polyposis with an OR of 11.2. It was not possible to detect an association between MUTYH mutations and breast cancer, obtaining a non-significant OR. In relation to other types of cancer, no significant association with heterozygous MUTYH mutations was found. Therefore, it cannot be affirmed that there is a relationship between the presence of MUTYH and breast cancer, one of the objectives of this study.
Similar to previous studies, in our setting, we have obtained a prevalence of MUTYH carriers of around 1–2%, with a predominance of G382D and Y179C mutations [16]. The prevalence of MUTYH in other studies has obtained values between 0.3 and 5.6% as illustrated in Table 5. Particularly interesting is the study of Kurian et al. 2021 with a sample size of about 15,000 patients who obtained a value of 1.4%. Therefore, our value of 1.8% is consistent with previous evidence.
Table 5. Some descriptive studies describing the prevalence of MUTYH alterations in breast cancer patients. BC = breast cancer, OC = ovarian cancer, BRCAx = without BRCA mutation, HBOCS = hereditary breast and ovarian cancer syndrome, EOBC = early onset breast cancer.
Former studies of the association between MUTYH variants and the risk of breast cancer have yielded conflicting results as shown in Table 6. However, studies with larger sample sizes do not seem to detect a relationship. This is consistent with the data from our work.
Table 6. Some case–control studies describing the association of MUTYH alterations with breast cancer patients. BC = breast cancer, BRCAx = without BRCA mutation, MUTYHmut = MUTYH mutation, P/LP = pathogenic/likely pathogenic, OR = odds ratio, SIR = standardized incidence ratio.
Interestingly, our study does not detect a relationship between MUTYH mutations and colorectal cancer. Nevertheless, there are studies that describe it. For example, Win et al. 2011, in monoallelic carriers, reported an elevated risk of colorectal cancer (OR 2.0), gastric cancer (OR 3.4), liver cancer (OR 3.1) and endometrial cancer (OR 2.3) but not in cancers of the breast, lung, kidney, prostate, pancreas or brain [33]. Win et al. 2014 described a slightly increased risk of colorectal cancer in patients with heterozygous MUTYH mutation, especially if there is a family history [39]. However, other studies have found no association between colon cancer and heterozygous mutations in MUTYH [40].
On the other hand, alterations in MUTYH are indeed related to colonic polyposis. But this usually occurs when the mutation is homozygous. We have obtained a significantly higher prevalence of heterozygous MUTYH mutations in patients with colonic polyposis and a significant and large OR of 11.2. Croitoru et al. 2004 showed that loss of heterozygosity phenomena could occur in patients with heterozygous MUTYH germline mutations and colonic polyps [41].
A strength of this study is that it is able to gather fourteen patients with breast cancer and MUTYH mutation. Most descriptive studies of hereditary breast cancer do not focus on MUTYH, but rather, it is a finding in the context of a panel of genes. Therefore, in these studies, they generally obtain fewer than 10 patients with breast cancer and MUTYH mutation.
There are several limitations. First, it is a single-center study, and MUTYH was studied with different methods in each patient. The choice of genes included in the gene panel varies depending on the diagnostic suspicion, thereby introducing a potential confounding variable in the extrapolation of our results. Moreover, the most frequent reason for detecting MUTYH alterations was in the context of a suspected HBOCS. This might be attributed to its prevalence as the primary motive for assessment within the Hereditary Cancer Unit. Another important aspect is to acknowledge the inherent ascertainment biases in a retrospective observational study in which the population is chosen specifically for genetic testing related to cancer susceptibility.

5. Conclusions

In summary, these data do not support a clinically significant association of breast cancer risk with monoallelic MUTYH carrier status. While multigene panel testing yields extensive and practical datasets, it is crucial to exercise caution when interpreting this information on an individual basis. This approach helps prevent the unintentional dissemination of potentially misleading clinical information that could harm patients. Additionally, when dealing with heterozygous mutations in the MUTYH gene, it is essential to interpret them with care, given their relatively frequent occurrence in the general population and the evolving insights into their significance.

Author Contributions

Conceptualization, J.P.-L., D.S.-C. and N.R.-S.; methodology, J.P.-L. and N.R.-S.; formal analysis, J.P.-L., I.R.-G. and D.J.-B.; investigation, J.P.-L., I.R.-G., D.J.-B., G.M.-M., M.A.-G., A.R.-L., L.R.-G., O.H.-G., A.G., A.P.-F., D.S.-C. and N.R.-S.; data curation, J.P.-L.; writing—original draft preparation, J.P.-L. and I.R.-G.; writing—review and editing, J.F. and A.G.; visualization, J.P.-L. and D.J.-B.; supervision, N.R.-S. and J.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hospital Universitario La Paz (protocol code PI-2861).

Data Availability Statement

De-identified individual data might be made available following publication by reasonable request to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F.; Bsc, M.F.B.; Me, J.F.; Soerjomataram, M.I.; et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Valle, L.; Vilar, E.; Tavtigian, S.V.; Stoffel, E.M. Genetic predisposition to colorectal cancer: Syndromes, genes, classification of genetic variants and implications for precision medicine. J. Pathol. 2018, 247, 574–588. [Google Scholar] [CrossRef]
  3. Al-Tassan, N.; Chmiel, N.H.; Maynard, J.; Fleming, N.; Livingston, A.L.; Williams, G.T.; Hodges, A.K.; Davies, D.R.; David, S.S.; Sampson, J.R.; et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat. Genet. 2002, 30, 227–232. [Google Scholar] [CrossRef] [PubMed]
  4. Jones, S.; Emmerson, P.; Maynard, J.; Best, J.M.; Jordan, S.; Williams, G.T.; Sampson, J.R.; Cheadle, J.P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C→T:A mutations. Hum. Mol. Genet. 2002, 11, 2961–2967. [Google Scholar] [CrossRef]
  5. Slupska, M.M.; Baikalov, C.; Luther, W.M.; Chiang, J.H.; Wei, Y.F.; Miller, J.H. Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J. Bacteriol. 1996, 178, 3885–3892. [Google Scholar] [CrossRef] [PubMed]
  6. Cheadle, J.P.; Sampson, J.R. Exposing the MYtH about base excision repair and human inherited disease. Hum. Mol. Genet. 2003, 12, R159–R165. [Google Scholar] [CrossRef]
  7. Russell, A.M.; Zhang, J.; Luz, J.; Hutter, P.; Chappuis, P.O.; Berthod, C.R.; Maillet, P.; Mueller, H.; Heinimann, K. Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients. Int. J. Cancer 2006, 118, 1937–1940. [Google Scholar] [CrossRef]
  8. VCV000005294.91-ClinVar-NCBI [Internet]. Available online: https://www.ncbi.nlm.nih.gov/clinvar/variation/5294/ (accessed on 22 May 2023).
  9. VCV000005293.82-ClinVar-NCBI [Internet]. Available online: https://www.ncbi.nlm.nih.gov/clinvar/variation/5293/ (accessed on 22 May 2023).
  10. Vogt, S.; Jones, N.; Christian, D.; Engel, C.; Nielsen, M.; Kaufmann, A.; Steinke, V.; Vasen, H.F.; Propping, P.; Sampson, J.R.; et al. Expanded Extracolonic Tumor Spectrum in MUTYH-Associated Polyposis. Gastroenterology 2009, 137, 1976–1985.e10. [Google Scholar] [CrossRef]
  11. Yoshida, R. Hereditary breast and ovarian cancer (HBOC): Review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer 2020, 28, 1167–1180. [Google Scholar] [CrossRef]
  12. Nielsen, M.; Franken, P.F.; Reinards, T.H.C.M.; Weiss, M.M.; Wagner, A.; van der Klift, H.; Kloosterman, S.; Houwing-Duistermaat, J.J.; Aalfs, C.M.; Ausems, M.G.E.M.; et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J. Med. Genet. 2005, 42, e54. [Google Scholar] [CrossRef]
  13. Maxwell, K.N.; Wubbenhorst, B.; D’Andrea, K.; Garman, B.; Long, J.M.; Powers, J.; Rathbun, K.; Stopfer, J.E.; Zhu, J.; Bradbury, A.R.; et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2 negative patients with early onset breast cancer. Genet. Med. 2015, 17, 630–638. [Google Scholar] [CrossRef] [PubMed]
  14. Le Page, F.; Randrianarison, V.; Marot, D.; Cabannes, J.; Perricaudet, M.; Feunteun, J.; Sarasin, A. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 2000, 60, 5548–5552. [Google Scholar] [PubMed]
  15. Fulk, K.; LaDuca, H.; Black, M.H.; Qian, D.; Tian, Y.; Yussuf, A.; Espenschied, C.; Jasperson, K. Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort. Fam. Cancer 2019, 18, 197–201. [Google Scholar] [CrossRef] [PubMed]
  16. Balaguer, F.; Leoz, M.; Carballal, S.; Moreira, L.; Ocaña, T. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl. Clin. Genet. 2015, 8, 95–107. [Google Scholar] [CrossRef] [PubMed]
  17. Kurian, A.W.; Hare, E.E.; Mills, M.A.; Kingham, K.E.; McPherson, L.; Whittemore, A.S.; McGuire, V.; Ladabaum, U.; Kobayashi, Y.; Lincoln, S.E.; et al. Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment. J. Clin. Oncol. 2014, 32, 2001–2009. [Google Scholar] [CrossRef] [PubMed]
  18. Ellingson, M.S.; Hart, S.N.; Kalari, K.R.; Suman, V.; Schahl, K.A.; Dockter, T.J.; Felten, S.J.; Sinnwell, J.P.; Thompson, K.J.; Tang, X.; et al. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res. Treat. 2015, 153, 435–443. [Google Scholar] [CrossRef]
  19. Lin, P.-H.; Kuo, W.-H.; Huang, A.-C.; Lu, Y.-S.; Lin, C.-H.; Kuo, S.-H.; Wang, M.-Y.; Liu, C.-Y.; Cheng, F.T.-F.; Yeh, M.-H.; et al. Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer. Oncotarget 2016, 7, 8310–8320. [Google Scholar] [CrossRef] [PubMed]
  20. Rummel, S.K.; Lovejoy, L.; Shriver, C.D.; Ellsworth, R.E. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res. Treat. 2017, 164, 593–601. [Google Scholar] [CrossRef]
  21. Kaur, R.P.; Shafi, G.; Benipal, R.P.S.; Munshi, A. Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients. Med. Oncol. 2018, 35, 1–9. [Google Scholar] [CrossRef]
  22. Meiss, A.E.; Thomas, M.; Modesitt, S.C.; Ring, K.L.; Atkins, K.A.; Mills, A.M. Clinicopathologic characterization of breast carcinomas in patients with non-BRCA germline mutations: Results from a single institution’s high-risk population. Hum. Pathol. 2018, 82, 20–31. [Google Scholar] [CrossRef]
  23. Oliver, J.; Quezada Urban, R.; Franco Cortés, C.A.; Díaz Velásquez, C.E.; Montealegre Paez, A.L.; Pacheco-Orozco, R.A.; Rojas, C.C.; Garcia-Robles, R.; Rivera, J.J.L.; Chaparro, S.G.; et al. Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach. Front Oncol. 2019, 9, 1429. [Google Scholar] [CrossRef] [PubMed]
  24. Rizzolo, P.; Silvestri, V.; Bucalo, A.; Zelli, V.; Valentini, V.; Catucci, I.; Zanna, I.; Masala, G.; Bianchi, S.; Spinelli, A.M.; et al. Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy. Front. Oncol. 2018, 8, 583. [Google Scholar] [CrossRef] [PubMed]
  25. Schneider, B.P.; Stout, L.A.; Philips, S.; Schroeder, C.; Scott, S.F.; Hunter, C.; Kassem, N.; Kiel, P.J.; Radovich, M. Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy. JCO Precis. Oncol. 2020, 4, 1109–1121. [Google Scholar] [CrossRef] [PubMed]
  26. Ryu, J.; Lee, H.; Cho, E.H.; Yoon, K.; Kim, M.; Joo, J.; Lee, E.; Kang, H.; Lee, S.; Lee, D.O.; et al. Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer. Cancer Sci. 2020, 111, 3912–3925. [Google Scholar] [CrossRef] [PubMed]
  27. Chen, B.; Zhang, G.; Li, X.; Ren, C.; Wang, Y.; Li, K.; Mok, H.; Cao, L.; Wen, L.; Jia, M.; et al. Comparison of BRCA versus non-BRCA germline mutations and associated somatic mutation profiles in patients with unselected breast cancer. Aging 2020, 12, 3140–3155. [Google Scholar] [CrossRef] [PubMed]
  28. Kurian, A.W.; Hughes, E.; Handorf, E.A.; Gutin, A.; Allen, B.; Hartman, A.-R.; Hall, M.J. Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women. JCO Precis. Oncol. 2017, 1, 1–12. [Google Scholar] [CrossRef] [PubMed]
  29. de Oliveira, J.M.; Zurro, N.B.; Coelho, A.V.C.; Caraciolo, M.P.; de Alexandre, R.B.; Cervato, M.C.; Minillo, R.M.; Neto, G.D.V.C.; Grivicich, I.; Oliveira, J.B. The genetics of hereditary cancer risk syndromes in Brazil: A comprehensive analysis of 1682 patients. Eur. J. Hum. Genet. 2022, 30, 818–823. [Google Scholar] [CrossRef]
  30. Tatineni, S.; Tarockoff, M.; Abdallah, N.; Purrington, K.S.; Assad, H.; Reagle, R.; Petrucelli, N.; Simon, M.S. Racial and ethnic variation in multigene panel testing in a cohort of BRCA1/2-negative individuals who had genetic testing in a large urban comprehensive cancer center. Cancer Med. 2022, 11, 1465–1473. [Google Scholar] [CrossRef]
  31. Rennert, G.; Lejbkowicz, F.; Cohen, I.; Pinchev, M.; Rennert, H.S.; Barnett-Griness, O. MutYH mutation carriers have increased breast cancer risk. Cancer 2012, 118, 1989–1993. [Google Scholar] [CrossRef]
  32. Beiner, M.E.; Zhang, W.W.; Zhang, S.; Gallinger, S.; Sun, P.; Narod, S.A. Mutations of the MYH gene do not substantially contribute to the risk of breast cancer. Breast Cancer Res. Treat. 2009, 114, 575–578. [Google Scholar] [CrossRef]
  33. Win, A.K.; Cleary, S.P.; Dowty, J.G.; Baron, J.A.; Young, J.P.; Buchanan, D.D.; Southey, M.C.; Burnett, T.; Parfrey, P.S.; Green, R.C.; et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int. J. Cancer 2011, 129, 2256–2262. [Google Scholar] [CrossRef]
  34. Out, A.A.; Wasielewski, M.; Huijts, P.E.A.; van Minderhout, I.J.H.M.; Houwing-Duistermaat, J.J.; Tops, C.M.J.; Nielsen, M.; Seynaeve, C.; Wijnen, J.T.; Breuning, M.H.; et al. MUTYH gene variants and breast cancer in a Dutch case–control study. Breast Cancer Res. Treat. 2012, 134, 219–227. [Google Scholar] [CrossRef] [PubMed]
  35. Win, A.K.; Reece, J.C.; Dowty, J.G.; Buchanan, D.D.; Clendenning, M.; Rosty, C.; Southey, M.C.; Young, J.P.; Cleary, S.P.; Kim, H.; et al. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int. J. Cancer 2016, 139, 1557–1563. [Google Scholar] [CrossRef] [PubMed]
  36. Jian, W.; Shao, K.; Qin, Q.; Wang, X.; Song, S.; Wang, X. Clinical and genetic characterization of hereditary breast cancer in a Chinese population. Hered. Cancer Clin. Pract. 2017, 15, 19. [Google Scholar] [CrossRef] [PubMed]
  37. Thompson, A.B.; Sutcliffe, E.G.; Arvai, K.; Roberts, M.E.; Susswein, L.R.; Marshall, M.L.; Torene, R.; Postula, K.J.V.; Hruska, K.S.; Bai, S. Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer. Fam. Cancer 2022, 21, 415–422. [Google Scholar] [CrossRef] [PubMed]
  38. Guindalini, R.S.C.; Viana, D.V.; Kitajima, J.P.F.W.; Rocha, V.M.; López, R.V.M.; Zheng, Y.; Freitas, É.; Monteiro, F.P.M.; Valim, A.; Schlesinger, D.; et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci. Rep. 2022, 12, 1–12. [Google Scholar] [CrossRef] [PubMed]
  39. Win, A.K.; Dowty, J.G.; Cleary, S.P.; Kim, H.; Buchanan, D.D.; Young, J.P.; Clendenning, M.; Rosty, C.; MacInnis, R.J.; Giles, G.G.; et al. Risk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer. Gastroenterology 2014, 146, 1208–1211.e5. [Google Scholar] [CrossRef]
  40. Lubbe, S.J.; Di Bernardo, M.C.; Chandler, I.P.; Houlston, R.S. Clinical Implications of the Colorectal Cancer Risk Associated With MUTYH Mutation. J. Clin. Oncol. 2009, 27, 3975–3980. [Google Scholar] [CrossRef]
  41. Croitoru, M.E.; Cleary, S.P.; Di Nicola, N.; Manno, M.; Selander, T.; Aronson, M.; Redston, M.; Cotterchio, M.; Knight, J.; Gryfe, R.; et al. Association Between Biallelic and Monoallelic Germline MYH Gene Mutations and Colorectal Cancer Risk. JNCI J. Natl. Cancer Inst. 2004, 96, 1631–1634. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Download PDF
Myeloproliferative Neoplasms: Diseases Mediated by Chronic Activation of Signal Transducer and Activator of Transcription (STAT) Proteins
Previous
Cultivable Microbiome Approach Applied to Cervical Cancer Exploration
Next