Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers
Abstract
:1. Introduction
2. Material and Methods
2.1. Patients
2.2. NGS Sequencing
2.3. Variants’ Classification
2.4. Statistical Analysis
3. Results
3.1. Multigene Panel Results
3.2. DSBs-HR Genes Variants and Related Phenotypes
3.2.1. ATM
3.2.2. RAD51C
3.3. MMR Genes Variants and Related Phenotypes
3.3.1. MLH1
3.3.2. MSH2
3.4. Cell Cycle Control Gene Variants and Related Phenotypes
CHEK2
3.5. DNA Repair Helicase Gene Variant-Related Phenotypes
RECQL
3.6. VUS Variants
3.7. Genotype-Phenotype Correlations
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Panel Gene | Syndrome | Main Pathway | Cancer Related | Reference |
---|---|---|---|---|
ATM | Ataxia Telangiectasia (AR) | DOUBLE STRAND BREAKS REPAIR (Homologous Recombination) | Breast, ovarian, pancreatic | [2,24,26] |
PALB2 | Fanconi Anemia (AR) | [24,26,27] | ||
MRE11A | Ataxia Telangiectasia-like disorder (AR) | Breast | [4,27] | |
RAD50 | Nijmegen breakage syndrome-like disorder (AR) | [4,28] | ||
BARD1 | [6] | |||
NBN | Nijmegen Breakage Syndrome (AR) | Breast, ovarian | [26] | |
BRIP1 | Fanconi Anemia (AR) | [7] | ||
RAD51C | [27] | |||
RAD51D | [27] | |||
STK11 | Peutz-Jeghers Syndrome (AD) | Colorectal, breast, pancreatic, gastric, small intestine, cervical, ovarian | [2,11] | |
MSH2 | Lynch Syndrome (AD) | MISMATCH REPAIR | Colorectal, endometrial, ovarian, gastric, urothelial, pancreaticobiliary, cutaneous sebaceous neo-plasms, brain | |
MLH1 | ||||
MSH6 | [2,26] | |||
PMS2 | ||||
EPCAM | ||||
MUTYH | MYH-Associated polyposis (AR) | BASE EXCISION REPAIR | Colorectal, duodenal, breast | [22] |
RECQL | DNA REPAIR (helicase) | breast | [29] | |
TP53 | Li-Fraumeni Syndrome (AD) | cell cycle control | Breast, sarcoma, brain, adrenocortical, leukemia, gastric | [2,26,27] |
PTEN | Cowden Syndrome (AD) | Colorectal, breast, endometrial, thyroid, renal | [2,16,26,27] | |
CHEK2 | Li-Fraumeni variant (AD) | Breast ovarian | [2,5,26] | |
CDH1 | Hereditary diffuse gastric cancer (AD) | Gastric, breast | [2,26,27] | |
CDK4 | Familial melanoma (AD) | Melanoma | [30] | |
CDKN2A | Melanoma, pancreatic | [2] | ||
SMAD4 | Juvenile polyposis Syndrome (AD) | Colorectal, Gastric | [17] | |
APC | Familial adenomatous polyposis (AD) | Colorectal, small intestine, ampullary, gastric, desmoid, thyroid | [13] |
n pts (F/M) | Mean Age Tot ± SD (Min–Max) | Mean Age at Onset Tot ± SD (Min–Max) | n Pts Onset ≤ 40 Years | Family History 1st, 2nd Degree (BC, OC, PrC, PC other C, multiple C) | |
---|---|---|---|---|---|
BC | 87 (87/0) | 54.39 ± 10.28 (36–83) | 49.25 ± 10.35 (30–82) | 16 | 82 (68, 18, 22, 9, 59, 14) |
Male BC | 7 (0/7) | 63.1 ± 11.8 (49–78) | 60.7 ± 13.2 (43–76) | 0 | 6 (4, 2, 1, 0, 6, 3) |
OC | 9 (9/0) | 59.56 ± 8.75 (46–71) | 52.33 ± 14.04 (28–68) | 2 | 9 (6, 3, 1, 0, 7, 0) |
PC | 3 (1/2) | 67.7 ± 2.1 (65–69) | 65.3 ± 0.6 (65–66) | 0 | 3 (1, 0, 1, 0, 3, 0) |
Fam | 7 (7/0) | 54.14 ± 8.63 (45–67) | - | - | 7 (5, 2, 3, 3, 6, 3) |
Total | 113 (104/9) | 55.65 ± 10.37 (36–83) | 50.24 ± 11.19 (27–82) | 19 | 107 (84, 25, 28, 12, 81, 20) |
Gene | Locus | Transcript | dbsnp | cDNA (HGVS) | Protein | Type of Variants | Gnomad | ACMG Classification | Count |
---|---|---|---|---|---|---|---|---|---|
APC | chr5:112176574 | NM_000038.5 | rs933729249 | c.5283C>G | p.(Asn1761Lys) | missense | / | VUS | 1 |
chr5:112176656 | rs1554086666 | c.5365G>C | p.(Val1789Leu) | missense | / | VUS | 1 | ||
chr5:112178958 | rs761133356 | c.7667C>T | p.(Ser2556Leu) | missense | 0.000012 | VUS | 1 | ||
ATM | chr11:108114838 | NM_000051.3 | rs771685059 | c.655T>C | p.(Cys219Arg) | missense | 0.00000796 | VUS | 1 |
chr11:108115727 | rs747727055 | c.875C>T | p.(Pro292Leu) | missense | 0.00000806 | LP | 1 | ||
chr11:108151895 | rs587776551 | c.3576G>A | p.(Lys1192=) | synonymous | 0.0000159 | P | 1 | ||
chr11:108163473 | rs1064795495 | c.4564G>A | p.(Gly1522Ser) | missense | 0.00000398 | VUS | 1 | ||
chr11:108164131 | rs368830730 | c.4703A>G | p.(His1568Arg) | missense | 0.0000398 | VUS | 1 | ||
chr11:108181006 | rs56399311 | c.5882A>G | p.(Tyr1961Cys) | missense | 0.0000398 | VUS | 1 | ||
chr11:108198368 | / | c.6976-4A>G | p.? | intronic | / | VUS | 1 | ||
chr11:108205751 | rs759779781 | c.8066A>G | p.(Glu2689Gly) | missense | 0.00000398 | VUS | 1 | ||
BARD1 | chr2:215661789 | NM_000465.3 | rs1060501308 | c.211T>A | p.(Cys71Ser) | missense | / | VUS | 1 |
BRIP1 | chr17:59937216 | NM_032043.2 | / | c.146G>A | p.(Gly49Glu) | missense | / | VUS | 1 |
chr17:59934442 | rs889877039 | c.356A>G | p.(Asn119Ser) | missense | 0.000137 | VUS | 1 | ||
CDH1 | chr16:68842738 | NM_004360.4 | rs786203207 | c.674T>C | p.(Ile225Thr) | missense | / | VUS | 1 |
CDKN2A | chr9:21970943 | NM_001195132.1 | rs587781733 | c.415G>A | p.(Gly139Ser) | missense | / | VUS | 1 |
CHEK2 | chr22:29121228 | NM_007194.3 | rs587781279 | c.444+3A>G | p.? | intronic | / | VUS | 1 |
chr22:29121087 | rs17879961 | c.470T>C | p.(Ile157Thr) | missense | 0.001 | LP | 2 | ||
chr22:29107974 | rs121908702 | c.715G>A | p.(Glu239Lys) | missense | / | VUS | 1 | ||
chr22:29106048 | rs730881687 | c.793-1G>A | p.(Asp265Thrfs*10) | splicing | / | P | 1 | ||
chr22:29091857 | rs555607708 | c.1100delC | p.(Thr367Metfs*15) | frameshift | 0.002 | P | 2 | ||
chr22:29091788 | rs200928781 | c.1169A>C | p.(Tyr390Ser) | missense | / | LP | 1 | ||
chr22:29091821 | rs267606211 | c.1136C>G | p.(Ser379Cys) | missense | / | LP | 1 | ||
chr22:29091123 | rs876659827 | c.1367C>T | p.(Ser456Leu) | missense | / | LP | 1 | ||
EPCAM | chr2:47602397 | NM_002354.2 | rs864622724 | c.450C>G | p.(His150Gln) | missense | / | VUS | 1 |
MLH1 | chr3:37083787 | NM_000249.3 | rs730881743 | c.1696T>C | p.(Tyr566His) | missense | / | LP | 1 |
MSH2 | chr2:47630512 | NM_000251.2 | rs587779113 | c.182A>C | p.(Gln61Pro) | missense | / | LP | 1 |
chr2:47702191 | rs41295288 | c.1787A>G | p.(Asn596Ser) | missense | 0.000318 | VUS | 1 | ||
chr2:47702251 | rs587779965 | c.1847C>G | p.(Pro616Arg) | missense | / | VUS | 1 | ||
MSH6 | chr2:48027323 | NM_000179.2 | rs1060502883 | c.2201T>A | p.(Val734Glu) | missense | / | VUS | 1 |
MUTYH | chr1:45798518 | NM_001128425.1 | rs890418965 | c.505-12T>G | p.? | intronic | / | VUS | 1 |
PALB2 | chr16:23614905 | NM_024675.3 | rs879254033 | c.3436C>A | p.(Gln1146Lys) | missense | / | VUS | 2 |
PMS2 | chr7:6045541 | NM_000535.6 | rs1583418527 | c.145G>A | p.(Ala49Thr) | missense | / | VUS | 1 |
chr7:6027143 | rs587782640 | c.1253C>T | p.(Ser418Phe) | missense | / | VUS | 1 | ||
chr7:6022480 | rs201671325 | c.2149G>A | p.(Val717Met) | missense | 0 | VUS | 1 | ||
RAD50 | chr5:131925536 | NM_005732.3 | / | c.1452+7T>G | p.? | intronic | / | VUS | 1 |
chr5:131939174 | / | c.2390G>A | p.(Arg797Lys) | missense | / | VUS | 1 | ||
RAD51C | chr17:56798178 | NM_058216.2 | rs587782702 | c.904+5G>T | p.(Val280Glyfs*11) | intronic | / | LP | 1 |
chr17:56801430 | rs730881932 | c.934C>T | p.(Arg312Trp) | missense | 0.00001 | LP | 1 | ||
chr17:56809908 | rs587781410 | c.1026+5_1026+7del | p.(Arg322Serfs*22) | intronic | / | LP | 1 | ||
RECQL | chr12:21643163 | NM_032941.2 | New | c.363_364del | p.(Cys122Leufs*43) | frameshift | / | P | 1 |
chr12:21643150 | rs1267616869 | c.377C>T | p.(Pro126Leu) | missense | / | VUS | 1 | ||
STK11 | chr19:1219382 | NM_000455.4 | rs369764220 | c.434A>G | p.(Glu145Gly) | missense | 0.0000134 | VUS | 1 |
ID Sample | Sex | Gene | P/LP Variants | Other Variants (VUS ) | Age (Years) | Age at Onset (Years) | Tumor Site | Histological Diagnosis | Grading | Other Personal History of Cancer (Onset in Years) | Family History of Cancer (n of 1st and 2nd Degree Affected Relatives) |
---|---|---|---|---|---|---|---|---|---|---|---|
P29 | F | ATM | c.875C>T p.(Pro292Leu) | RECQL c.377C>T p.(Pro126Leu) | 44 | 43 | breast (left) | DCIS | G1 | M(42) | M (1); CNSC (1) |
P89 | M | ATM | c.3576G>A p.(Lys1192=) | - | 66 | 66 | pancreas | Adenocarcinoma | na | GC(45) | GC (8) |
P113 | F | RAD51C | c.904+5G>T p.(Val280Glyfs*11) | - | 46 | 43 | ovary | HSGC | na | - | NHL(1); OC (2), TC (1) |
P33 | F | RAD51C | c.934C>T p.(Arg312Trp) | c.1847C>G p.(Pro616Arg) | 47 | 35 | breast (left); breast (right) | CLI; IDC | G3 | - | BC (1 + 1); CC (1); BlC (1), CNSC(1) |
P110 | F | RAD51C | c.1026+5_1026+7del p.(Arg322Serfs*22) | - | 53 | 51 | ovary | HSGC | na | - | OC (1), GC (1), EC (1); PrC (1); LC (1) |
P67 | F | MLH1 | c.1696T>C p.(Tyr566His) | - | 39 | 39 | breast (right) | IDC | G3 | - | BC (1); PrC (2) |
P53 | F | MSH2 | c.182A>C p.(Gln61Pro) | - | 58 | 56 | breast (left) | IDC | G3 | - | PrC (3 + 1), UC (1); unk C (1) |
P90 | M | RECQL | c.363_364del p.(Cys122Leufs*43) | - | 72 | 59 | breast (right) | IDC | G2 | PrC | BC (1); LC (1) |
P18 | F | CHEK2 | c.470T>C p.(Ile157Thr) | - | 47 | 42 | breast (left) | CDI | G2 | CC, OC, GC | PrC (1); RC (1) |
P46 | F | CHEK2 | c.470T>C p.(Ile157Thr) | PMS2 c.145G>A p.(Ala49Thr) | 51 | 50 | breast (right) | DCIS | G1 | - | OC (1); UC (1); RC (1) |
P68 | F | CHEK2 | c.793-1G>A p.(Asp265Thrfs*10) | - | 47 | 27 | tyroid | papillary | na | - | BC (1), PrC(1 + 3); GC (1); LC (1); S(1) |
P111 | F | CHEK2 | c.1100del p.(Thr367Metfs*15) | - | 56 | 50 | breast (bil) | IDC | G2 (right) G1 (left) | - | BC (1) |
P112 | F | CHEK2 | c.1100del p.(Thr367Metfs*15) | - | 66 | 64 | breast (bil) | IDC | G3 (right) G2 (left) | dML | BC (2 + 1), unk C (1) |
P12 | F | CHEK2 | c.1136C>G p.(Ser379Cys) | RAD50 c.1452+7T>G | 49 | 49 | skin/foot | melanoma | na | - | BC (2 + 1); GC (1); PC (1); LC (2), head-neck C (1) |
P60 | M | CHEK2 | c.1367C>T p.(Ser456Leu) | - | 71 | 71 | breast | DCIS | G2 | - | BC (2 + 1), OC (1 + 1); LC (1) |
P04 | F | CHEK2 | c.1169A>C p.(Tyr390Ser) | - | 53 | 52 | uterus | Mullerian sarcoma | na | - | BC (2), CC (3 + 1) |
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Germani, A.; Petrucci, S.; De Marchis, L.; Libi, F.; Savio, C.; Amanti, C.; Bonifacino, A.; Campanella, B.; Capalbo, C.; Lombardi, A.; et al. Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers. J. Clin. Med. 2020, 9, 3003. https://doi.org/10.3390/jcm9093003
Germani A, Petrucci S, De Marchis L, Libi F, Savio C, Amanti C, Bonifacino A, Campanella B, Capalbo C, Lombardi A, et al. Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers. Journal of Clinical Medicine. 2020; 9(9):3003. https://doi.org/10.3390/jcm9093003
Chicago/Turabian StyleGermani, Aldo, Simona Petrucci, Laura De Marchis, Fabio Libi, Camilla Savio, Claudio Amanti, Adriana Bonifacino, Barbara Campanella, Carlo Capalbo, Augusto Lombardi, and et al. 2020. "Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers" Journal of Clinical Medicine 9, no. 9: 3003. https://doi.org/10.3390/jcm9093003
APA StyleGermani, A., Petrucci, S., De Marchis, L., Libi, F., Savio, C., Amanti, C., Bonifacino, A., Campanella, B., Capalbo, C., Lombardi, A., Maggi, S., Mattei, M., Osti, M. F., Pellegrini, P., Speranza, A., Stanzani, G., Vitale, V., Pizzuti, A., Torrisi, M. R., & Piane, M. (2020). Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers. Journal of Clinical Medicine, 9(9), 3003. https://doi.org/10.3390/jcm9093003